Autosomal Dominant Nonsyndromic Hearing Loss 41

Mendelian MONDO:0011994 Pathograph 12 Show in embeddings browser Autosomal Dominant Nonsyndromic Hearing Loss

DFNA41 is dominantly inherited, delayed-onset, progressive sensorineural hearing loss caused by heterozygous variants in P2RX2, which encodes the P2X2 subunit of an ATP-gated cation channel expressed on sensory and supporting cells of the cochlea. Onset in the original six-generation kindred was between 25 and 35 years, and hearing loss was fully penetrant and involved all frequencies. The reason to curate this entry rather than treat it as one more dominant deafness locus is that P2X2 is not a structural protein of the hair bundle. It is part of a feedback system. Rising sound levels cause ATP release into the endolymphatic compartment, ATP opens P2X2 channels on the epithelium lining that compartment, and the resulting conductance turns down the gain of the cochlear amplifier. That is what a temporary threshold shift is: not damage, but a protective adaptation to loud sound. P2RX2-null mice do not develop the temporary threshold shift that wild-type mice develop under sustained 85 dB noise, and at higher levels they sustain more permanent damage than wild-type mice do. So DFNA41 is a disorder of a protective mechanism, and its clinical signature follows from that. Hearing declines on its own, but noise exposure makes it worse, and this has been observed on both sides of the same experiment: P2RX2-null mice exposed early to continuous moderate noise had high-frequency hearing loss as young adults, and among heterozygous family members carrying p.Val60Leu, noise exposure exacerbated high-frequency hearing loss in young adulthood. The environmental interaction is therefore modelled here as a pathograph edge rather than left as prose, because for this disease it is a mechanism rather than a lifestyle note. The molecular defect for the founding allele is well characterised. P2RX2 p.Val60Leu abolishes both hallmark properties of the receptor, the ATP-evoked inward current and the ATP-stimulated macropore permeability, and coexpressing mutant with wild-type subunits significantly reduces ATP-activated membrane permeability - which is what makes a heterozygous allele dominant in a channel assembled from three subunits. There is a genome-editing proof of concept. AAV-delivered SaCas9 disrupting the mutant allele in the mature inner ear of a knock-in mouse restored auditory and vestibular function long-term, and specifically protected against noise hypersensitivity, which says the environmental arm of this disease is itself addressable rather than only its baseline hearing loss. The authors frame the novelty as extending editing beyond hearing rescue; whether it is the first such demonstration is their claim to make, not this entry's. Intervention at a juvenile stage widened the frequency range rescued. One recent finding unsettles the "nonsyndromic" label. A five-generation Chinese kindred carrying the same p.Val60Leu allele was tested for pain perception quantitatively, and heterozygotes showed hyperalgesia. P2X2 receptors sit on sensory neurons and purinergic signalling has an established role in nociception, so this is not a surprising place for the channel to matter - but no earlier DFNA41 report looked for it, so how general it is cannot be stated. That family also had earlier onset and worse hearing than the original ones on the same allele, which is a reminder that the 25-to-35-year window is a property of the founding kindred rather than of the variant.

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Inheritance
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Pathophys.
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Phenotypes
3
Gaps
12
Pathograph
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Genes
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Medical Actions
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Models
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References
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Deep Research
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Inheritance

1
Autosomal dominant HP:0000006
Heterozygous P2RX2 variants, fully penetrant in the founding six-generation kindred. Dominance is mechanistically accounted for rather than merely observed: P2X2 receptors are trimeric, so a mutant subunit incorporated into a heteromeric channel reduces the function of the whole assembly, and this was measured directly in coexpression experiments.
Autosomal dominant inheritance
Show evidence (3 references)
PMID:23345450 SUPPORT Human Clinical
"Genomic analysis of dominantly inherited, progressive sensorineural hearing loss DFNA41 in a six-generation kindred revealed a rare heterozygous allele, P2RX2 c.178G > T (p.V60L), at chr12:133,196,029, which cosegregated with fully penetrant hearing loss in the index family, and also appeared in..."
The founding pedigree, the allele, and full penetrance in two families.
PMID:23345450 SUPPORT In Vitro
"Coexpression of mutant and WT P2X(2) receptor subunits significantly reduced ATP-activated membrane permeability."
The mechanistic basis of dominance in a multimeric channel, measured rather than assumed.
PMID:24211385 SUPPORT Human Clinical
"We performed a linkage analysis in a large Italian family with a dominant pattern of inheritance showing a significant 3.31 LOD score in a 2Mb region overlapping with the DNFA41 locus."
Independent linkage evidence for dominant inheritance at the same locus.
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Discussions and Knowledge Gaps

3
How much noise is too much for a P2RX2 carrier? Is there a dose below which a carrier is no worse off than a non-carrier, and does hearing conservation started before onset change the trajectory?
KNOWLEDGE GAP dfna41_carrier_noise_dose_response
Attached to
environmental#Occupational and recreational noise exposure treatments#Hearing Conservation and Noise Avoidance phenotypes#Noise-Exacerbated High-Frequency Hearing Impairment
This entry curates noise avoidance as a treatment on the strength of an association and a mechanism, and that is the weakest treatment claim in the file. The evidence is that exposed carriers did worse than unexposed ones in one family, and that null mice exposed to a laboratory protocol lost high frequencies. Neither tells a 22-year-old carrier whether to change career, and neither establishes that protection helps. The gap is quantitative and it is answerable. Occupational noise exposure limits are built on population dose-response data in people with intact purinergic adaptation; a carrier has, by hypothesis, a left-shifted curve, but nobody has measured where. The mouse work gives a hint that the shift is real at moderate levels, since the difference between null and wild-type appears at 85 dB - below the level at which additional damage processes take over - which is squarely inside the range of ordinary occupational exposure rather than at the extremes. What would settle it is a carrier cohort with dosimetry rather than recalled exposure, audiometry over years, and non-carrier relatives as controls. The founding kindred is six generations deep and has already been followed for ten years, so the ascertainment problem is mostly solved. Until then the counselling advice in this entry should be read as mechanistically motivated rather than evidence-based, which is how the treatment entry states it.
Proposed experiments
Longitudinal noise dosimetry in P2RX2 carriers and non-carrier relatives
exp_dfna41_carrier_noise_dosimetry_cohort
Enrol carriers and genotype-negative relatives from known DFNA41 kindreds, measure cumulative noise exposure by personal dosimetry rather than by questionnaire, and follow pure tone and extended high-frequency audiometry annually. Model threshold change against cumulative dose separately by genotype to estimate whether the exposure-response curve is shifted and by how much.
Would support
phenotypes#Noise-Exacerbated High-Frequency Hearing Impairment
Would refute
phenotypes#Noise-Exacerbated High-Frequency Hearing Impairment
Supporting outcome
  • Carriers show a steeper threshold-versus-dose slope than non-carrier relatives, with separation beginning at exposures within current occupational limits, which would justify genotype-specific exposure advice and give a number to give patients.
Refuting outcome
  • Carrier and non-carrier slopes are indistinguishable and the carrier decline is independent of measured dose, which would mean the reported exacerbation reflects recall bias or confounding and that noise avoidance should be dropped from this entry as a mechanism-specific recommendation.
Show evidence (4 references)
PMID:23345450 SUPPORT Human Clinical
"Similarly, among family members heterozygous for P2RX2 p.V60L, noise exposure exacerbated high-frequency hearing loss in young adulthood."
Graded PARTIAL: an exposure-outcome association without exposure quantification, which is exactly the limitation the gap is about.
PMID:23592720 SUPPORT Model Organism
"In mice null for the P2RX2 gene (encoding the P2X2 receptor subunit), sustained 85-dB noise failed to elicit the TTS that wild-type (WT) mice developed."
Locates the divergence at a specific, ordinary sound level, which is what makes the dose question concrete rather than abstract.
PMID:23592720 SUPPORT Model Organism
"At higher sound levels (≥95 dB), additional processes dominated TTS, and P2RX2-null mice were more vulnerable than WT mice to permanent hearing loss due to hair cell synapse disruption."
Shows that the relationship between genotype and sound level is not monotonic in kind: different processes dominate at different intensities, so a single exposure limit may not be the right answer.
+ 1 more reference
The purinergic adaptation mechanism was established in homozygous P2rx2 null mice, but DFNA41 patients are heterozygous for a subunit that poisons trimeric channels partially. Is adaptation abolished in carriers, or merely reduced, and does that difference change what noise does to them?
HUMAN MODEL MISMATCH dfna41_null_versus_heterozygous_mechanism
Attached to
pathophysiology#Loss of Purinergic Adaptation to Elevated Sound Levels animal_models#P2rx2 null mouse
The two halves of this entry's mechanism come from different genotypes. The adaptation node rests on null mice, where the conductance is absent outright. Patients carry one mutant allele in a channel built from three subunits, and the measured consequence of that is a significant reduction in ATP-activated permeability on coexpression - a reduction, not an abolition. So the human condition is a partial loss of a graded protective mechanism, and the model that defined the mechanism is a complete loss of it. This matters for more than tidiness. If adaptation in carriers is reduced but present, there may be a sound level below which it still engages, which is precisely the dose question a carrier needs answered. If it is effectively abolished at ordinary sound levels despite the residual wild-type channels, the carrier is in the same position as the null mouse and the advice is simpler and stricter. Nobody has measured noise-induced temporary threshold shift in a P2rx2 V60L heterozygous mouse, which is the obvious experiment and uses a model that already exists. The gene-editing study bears on this indirectly and encouragingly: rescuing the heterozygote restored noise resistance, which implies the heterozygous state does have a noise phenotype to rescue. But that is an endpoint measurement, not a measurement of the adaptation itself.
Proposed experiments
Temporary threshold shift measurement in P2rx2 V60L heterozygous mice
exp_dfna41_tts_in_heterozygous_knockin
Run the same graded sound-level protocol used in the null study - sustained exposure at 85 dB and at 95 dB with auditory brainstem response and distortion product otoacoustic emission recordings before, during and after - in P2rx2 V60L heterozygous knock-in mice, wild-type littermates, and P2rx2 nulls in the same experiment, at an age before the knock-in has lost baseline hearing.
Would support
pathophysiology#Loss of Purinergic Adaptation to Elevated Sound Levels
Would refute
pathophysiology#Loss of Purinergic Adaptation to Elevated Sound Levels
Supporting outcome
  • Heterozygotes show a reduced but measurable temporary threshold shift, intermediate between wild-type and null, which would establish adaptation as graded with gene dosage and would give a sound level at which carrier protection still engages.
Refuting outcome
  • Heterozygotes are indistinguishable from wild-type in threshold shift while still developing progressive hearing loss, which would mean the adaptation defect is not the mechanism of DFNA41 in carriers and would push the entry's centre of gravity toward the synaptic node instead.
Show evidence (3 references)
PMID:23345450 SUPPORT In Vitro
"Coexpression of mutant and WT P2X(2) receptor subunits significantly reduced ATP-activated membrane permeability."
The human genetic state is partial loss, quantified. That is the mismatch with the null model.
PMID:23592720 SUPPORT Model Organism
"P2RX2-null mice lacked ATP-gated conductance across the cochlear partition, including loss of ATP-gated inward current in hair cells."
The model state is complete loss, also measured. Setting the two quotes side by side is the substance of the mismatch.
PMID:41090360 SUPPORT Model Organism
"Editing further protects P2rx2V61L/+ mice from hypersensitivity to noise-induced hearing loss, a phenotype also observed in patients with DFNA41."
Graded PARTIAL: indirect evidence that the heterozygote does have a noise phenotype, since it can be rescued, but it does not measure purinergic adaptation in that genotype.
P2RX2 is classified Moderate rather than Definitive for dominant nonsyndromic hearing loss. What would move it, and does the strength of the mechanistic evidence make the human genetic evidence look better than it is?
KNOWLEDGE GAP dfna41_gene_disease_validity
Attached to
genetic#P2RX2 disease#Autosomal Dominant Nonsyndromic Hearing Loss 41
This entry is mechanistically rich and genetically thin, and the two can be mistaken for one another. The purinergic adaptation story rests on a null mouse, a knock-in mouse, a genome-editing rescue and direct electrophysiology - as good a mechanistic case as most deafness genes have. The human case rests on three missense variants in four probands, which is why ClinGen's Hearing Loss expert panel classified the gene-disease relationship Moderate in 2018 and left it at Moderate on reevaluation in 2022 even after adding a new case and a new mouse model. The panel's own framing is worth keeping in view: more evidence is needed to establish the relationship definitively, and no convincing contradictory evidence has emerged. That is not scepticism about the gene, it is a statement that segregation and case counts have not accumulated. What would move the classification is more independent probands with segregation, which for an adult-onset dominant condition means finding families rather than waiting for them. Practically, the caution belongs at the point of variant interpretation rather than in the mechanism. A novel P2RX2 missense variant in an isolated adult with progressive high-frequency loss and a noise history is exactly the situation in which a Moderate gene-disease classification should restrain a pathogenic call - and it is also the situation this entry's diagnosis section warns is easy to misattribute in the other direction. Both errors are available, and this entry deliberately does not resolve that tension by hiding either half.
Show evidence (4 references)
CGGV:assertion_c1dae6b6-4ed7-4c5a-ba4e-bcfaba026be8-2022-09-21T160000.000Z SUPPORT Other
"In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged."
The panel's summary judgement, in its own words.
CGGV:assertion_c1dae6b6-4ed7-4c5a-ba4e-bcfaba026be8-2022-09-21T160000.000Z SUPPORT Other
"Three missense variants that have been reported in four probands in four publications are included in this curation"
The size of the human genetic evidence base, which is the specific thing that is thin - not the mechanism.
CGGV:assertion_c1dae6b6-4ed7-4c5a-ba4e-bcfaba026be8-2022-09-21T160000.000Z SUPPORT Other
"Although a new case with hearing loss (29986705) and a new knock-in mouse model with progressive hearing loss (33791800) were scored, the classification did not change (SOP Version 9)."
The 2022 reevaluation, which is informative about what does not move a classification: an additional case and the allele-matched knock-in this entry relies on were both scored and left it at Moderate.
+ 1 more reference
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Pathophysiology

3
P2X2 Receptor Loss of Function
Heterozygous P2RX2 alleles that cripple the ATP-gated channel. The best-characterised is p.Val60Leu, which abolishes both defining properties of P2X2 receptors: the ATP-evoked inward current and the ATP-stimulated macropore permeability measured as loss of ATP-activated FM1-43 labelling. Other reported alleles are p.Gly353Arg in an Italian family, predicted by comparative modelling to destabilise the fold near the region controlling channel gating, p.Asp201Tyr in a Japanese family, and a stop-loss variant p.Ter350Glu in an Iranian family that would extend translation into the 3-prime untranslated region and yield a longer protein. The dominant mechanism is subunit poisoning rather than simple haploinsufficiency. P2X2 channels assemble from three subunits, and coexpressing mutant with wild-type subunits significantly reduced ATP-activated permeability, so a single mutant allele degrades the function of channels that also contain wild-type subunits.
P2RX2 hgnc:15459 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves P2RX2 (hgnc:15459). hgnc:15459 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context P2RX2 hgnc:15459 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns P2RX2 (hgnc:15459). hgnc:15459 is a gene from the HUGO Gene Nomenclature Committee. allele_type: SNV variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: DOMINANT_NEGATIVE
Heterozygous germline missense and stop-loss alleles. Recorded as DOMINANT_NEGATIVE rather than LOSS_OF_FUNCTION because the mutant subunit does not merely fail: it is incorporated into a trimeric channel alongside wild-type subunits and degrades that channel's function, which was measured directly in coexpression and is the reading ClinGen's Hearing Loss Gene Curation Expert Panel also takes.
extracellularly ATP-gated monoatomic cation channel activity GO:0004931 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased extracellularly ATP-gated monoatomic cation channel activity (GO:0004931). GO:0004931 is a molecular function from the Gene Ontology. ↓ DECREASED
Experimental models
Patient-derived P2RX2 p.Val60Leu hiPSC lines and their CRISPR homozygous isogenic control IPSC DERIVED MODEL Establishes the p.Val60Leu allele at two dosages in a human genetic background: the patients' own heterozygous state, and an engineered homozygote as a control for gene function.
Downstream
Loss of Purinergic Adaptation to Elevated Sound Levels
Inner Hair Cell and Ribbon Synapse Disorganisation
Show evidence (4 references)
PMID:23345450 SUPPORT In Vitro
"P2RX2 p.V60L abolishes two hallmark features of P2X(2) receptors: ATP-evoked inward current response and ATP-stimulated macropore permeability, measured as loss of ATP-activated FM1-43 fluorescence labeling."
The direct electrophysiological and permeability measurement of the founding allele.
PMID:23345450 SUPPORT Human Clinical
"The mutation was absent from more than 7,000 controls."
Population-frequency evidence supporting pathogenicity of the founding allele.
PMID:24211385 SUPPORT Computational
"Visual inspection of the protein structure as obtained from comparative modeling suggests that substitution of the small glycine residue with a charged bulky residue such as an arginine that is close to the 'neck' of the region responsible for ion channel gating should have a high energetic cost..."
The structural rationale for the second reported allele. Graded COMPUTATIONAL because it is comparative modelling, not a functional assay.
+ 1 more reference
Loss of Purinergic Adaptation to Elevated Sound Levels
The core mechanism, and the one that makes DFNA41 unlike the structural deafness genes. As sound level rises, ATP is released from the tissues of the cochlear partition and activates P2X2 receptors distributed on the epithelial cells lining the endolymphatic compartment. The resulting conductance reduces the gain of the cochlear amplifier, which appears in auditory brainstem responses as a temporary threshold shift. This is an adaptive response to loud sound rather than injury. P2RX2-null mice do not develop that shift under sustained 85 dB noise, and the supporting measurements show the failure is upstream in the intended place: outer hair cell distortion product emissions are suppressed by noise significantly more in wild-type than in null mice, and suprathreshold response gain falls more in wild-type animals. Losing the adaptation is not protective; it removes a brake. At 95 dB and above the nulls are more vulnerable than wild-type mice to permanent hearing loss through hair cell synapse disruption.
cochlear outer hair cell CL:0000601 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cochlear outer hair cell (CL:0000601). CL:0000601 is a cell type from the Cell Ontology. supporting cell CL:0000630 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves supporting cell (CL:0000630). CL:0000630 is a cell type from the Cell Ontology.
purinergic nucleotide receptor signaling pathway GO:0035590 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased purinergic nucleotide receptor signaling pathway (GO:0035590). GO:0035590 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
P2rx2 null mouse Mouse recapitulates Defines the mechanism, with the conductance measurement, the behavioural threshold measurement and the supporting emission and gain data all in one system. Nothing equivalent can be measured in patients.
P2rx2 V61L knock-in mouse treated with AAV-delivered SaCas9 Mouse rescues The forward test of the mechanism. Removing the mutant allele restores not just hearing but specifically the resistance to noise, which is the functional signature of the purinergic adaptation this entry places at the centre of the disease. That the noise phenotype rescues separately is the strongest available evidence that it is mechanistically distinct from the baseline progressive loss rather than a consequence of it.
Downstream
Inner Hair Cell and Ribbon Synapse Disorganisation
Noise-Exacerbated High-Frequency Hearing Impairment
Show evidence (5 references)
PMID:23592720 SUPPORT Model Organism
"We show that ATP-gated ion channels assembled from P2X2 receptor subunits in the cochlea are necessary for the development of temporary threshold shift (TTS), evident in auditory brainstem response recordings as sound levels rise."
The central claim of this node, established in the null mouse.
PMID:23592720 SUPPORT Model Organism
"In mice null for the P2RX2 gene (encoding the P2X2 receptor subunit), sustained 85-dB noise failed to elicit the TTS that wild-type (WT) mice developed."
The specific loss-of-adaptation result at a moderate, non-damaging sound level.
PMID:23592720 SUPPORT Model Organism
"ATP released from the tissues of the cochlear partition with elevation of sound levels likely activates the broadly distributed P2X2 receptors on epithelial cells lining the endolymphatic compartment."
The proposed signalling route. Recorded with the authors' own hedge intact, since the release step is inferred rather than directly imaged.
+ 2 more references
Inner Hair Cell and Ribbon Synapse Disorganisation
The structural correlate seen in the knock-in mouse carrying the human founding allele. Abnormal inner hair cell and ribbon synapse morphology appears progressively, which the authors read as P2rx2 having a role in where ribbon synapses sit in the membrane. This is consistent with the finding in null mice that above the adaptive range, permanent loss occurs through hair cell synapse disruption. The node is drawn with an unknown-intermediate link from the channel defect because nothing connects loss of ATP-gated conductance to synaptic placement mechanistically; the two are observed in the same animals, not shown to be steps in one chain.
cochlear inner hair cell CL:0000589 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cochlear inner hair cell (CL:0000589). CL:0000589 is a cell type from the Cell Ontology.
Animal models
P2rx2 V60L knock-in mouse Mouse recapitulates The only system in which inner hair cell and ribbon synapse morphology has been examined for this disease - no human DFNA41 temporal bone study exists, and the zebrafish and null-mouse work reports neither. It is allele-matched and heterozygous, so it reproduces the human genetic state rather than approximating it with a null.
Downstream
Progressive Sensorineural Hearing Impairment
Show evidence (2 references)
PMID:33791800 SUPPORT Model Organism
"Abnormal morphology of the inner hair cells and ribbon synapses was progressively observed in KI animals suggesting that P2rx2 plays a role in the membrane spatial location of the ribbon synapses."
The structural finding in the allele-matched knock-in, stated with the authors' hedge about what it suggests.
PMID:23592720 SUPPORT Model Organism
"At higher sound levels (≥95 dB), additional processes dominated TTS, and P2RX2-null mice were more vulnerable than WT mice to permanent hearing loss due to hair cell synapse disruption."
Graded PARTIAL because it attributes permanent noise damage in nulls to synapse disruption without measuring synapse morphology; it corroborates the knock-in finding rather than independently establishing it.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Autosomal Dominant Nonsyndromic Hearing Loss 41 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

7
Ear 1
Tinnitus HP:0000360 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tinnitus (HP:0000360). HP:0000360 is a phenotype from the Human Phenotype Ontology.
frequency is deliberately absent. The source says "in one family" out of the four probands curated, which is a count of families rather than of affected individuals, so there is no patient denominator to grade a FrequencyEnum band against.
Show evidence (1 reference)
CGGV:assertion_c1dae6b6-4ed7-4c5a-ba4e-bcfaba026be8-2022-09-21T160000.000Z SUPPORT Other
"The hearing loss in these families had a postlingual onset, was progressive, and co-occurred with tinnitus in one family."
The expert-panel summary of the reported DFNA41 families, which is where the tinnitus is recorded. Graded OTHER because a ClinGen curation is an expert reading of other people's cases rather than a study reporting its own.
Nervous System 1
Hyperalgesia Dysesthesia HP:0012534 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperalgesia, annotated with Dysesthesia (HP:0012534). HP:0012534 is a phenotype from the Human Phenotype Ontology.
HPO has no separate term for hyperalgesia. HP:0012534 carries Hyperalgesia and Hyperpathia as exact synonyms and its definition names both, so the binding is the one HPO intends, but the canonical label is Dysesthesia and its text describes pain from a nonpainful stimulus, which is closer to allodynia. preferred_term carries the accurate finding. frequency is deliberately absent rather than set to a low band. Pain perception was measured in one family and no other DFNA41 report tested it, so there is no denominator to grade against, and FrequencyEnum has no value meaning "not established".
Show evidence (1 reference)
PMID:39258340 SUPPORT Human Clinical
"We quantitatively evaluated the pain perception ability of some members using the Pain Vision PS-2100 system, and further found an interesting clinical manifestation, that is, hyperalgesia, in heterozygotes for P2RX2 p.V60L."
The measurement and the genotype it was made in. Quantitative rather than symptom-report, which matters for a finding this easy to dismiss.
Other 5
Progressive Sensorineural Hearing Impairment OBLIGATE HP:0000408 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive sensorineural hearing impairment (HP:0000408). HP:0000408 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31593348 SUPPORT Human Clinical
"Progressive hearing impairment was confirmed by history and by audiological follow-up testing in all the patients."
Progression established prospectively rather than by recall, in a ten-year follow-up of the founding family.
PMID:31593348 SUPPORT Human Clinical
"All affected subjects had bilateral sensorineural hearing loss involving all frequencies with some significant gender differences."
Bilaterality and the all-frequency configuration in the same cohort.
Adult-Onset Hearing Impairment FREQUENT Adult onset sensorineural hearing impairment HP:0008615 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Adult-onset sensorineural hearing impairment, annotated with Adult onset sensorineural hearing impairment (HP:0008615). HP:0008615 is a phenotype from the Human Phenotype Ontology.
The 25-to-35-year window is the RESULTS statement of PMID:31593348, the ten-year follow-up of the founding kindred. Yan 2013 (PMID:23345450) reports a 12-to-20-year window for what is the same family, so the two published descriptions of one kindred disagree; the later, prospectively followed report is the one cited here. frequency is FREQUENT rather than VERY_FREQUENT for that reason. Adult onset is not established in 80 to 99 percent of carriers: one published reading of the founding kindred puts onset in adolescence, and the Chinese p.Val60Leu family had onset earlier still. What is uncontested across every report is postlingual onset, which is curated separately and graded OBLIGATE; adulthood specifically is the part the sources disagree about.
Show evidence (2 references)
PMID:31593348 SUPPORT Human Clinical
"The onset of hearing loss was between age 25 and 35 years."
The age-at-onset range in the best-characterised family.
PMID:39258340 SUPPORT Human Clinical
"Despite carrying the same variant, the affected members in this family appear to present with earlier-onset hearing loss and poorer hearing compared to the original DFNA41 families."
Graded PARTIAL because it qualifies the onset window rather than confirming it. A later five-generation Chinese kindred carrying the same p.Val60Leu allele had earlier onset and worse hearing than the original families, so the 25-to-35-year range is not a property of the allele.
Bilateral Sensorineural Hearing Impairment OBLIGATE HP:0008619 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bilateral sensorineural hearing impairment (HP:0008619). HP:0008619 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31593348 SUPPORT Human Clinical
"All affected subjects had bilateral sensorineural hearing loss involving all frequencies with some significant gender differences."
Bilateral involvement in all affected subjects of the prospectively followed kindred, which is what makes OBLIGATE rather than a lower band the right grade.
Noise-Exacerbated High-Frequency Hearing Impairment FREQUENT High-frequency sensorineural hearing impairment HP:0001757 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High-frequency sensorineural hearing impairment (HP:0001757). HP:0001757 is a phenotype from the Human Phenotype Ontology.
Frequency is FREQUENT rather than higher because it is conditional on exposure: the phenotype is reported in family members who had noise exposure, and no reported series quantifies what fraction of all carriers that is.
Show evidence (2 references)
PMID:23345450 SUPPORT Human Clinical
"Similarly, among family members heterozygous for P2RX2 p.V60L, noise exposure exacerbated high-frequency hearing loss in young adulthood."
The human observation of the gene-environment interaction.
PMID:23345450 SUPPORT Model Organism
"P2RX2-null mice developed severe progressive hearing loss, and their early exposure to continuous moderate noise led to high-frequency hearing loss as young adults."
The matching result in mice, where exposure could be controlled rather than recalled.
Postlingual Sensorineural Hearing Impairment OBLIGATE HP:0008596 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Postlingual sensorineural hearing impairment (HP:0008596). HP:0008596 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
CGGV:assertion_c1dae6b6-4ed7-4c5a-ba4e-bcfaba026be8-2022-09-21T160000.000Z SUPPORT Other
"The hearing loss in these families had a postlingual onset, was progressive, and co-occurred with tinnitus in one family."
The expert panel's summary across all four curated probands, which is the broadest statement of postlingual onset available. Graded OTHER because a ClinGen curation reads other people's cases rather than reporting its own.
🧬

Genetic Associations

1
P2RX2
Gene: P2RX2 hgnc:15459 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is P2RX2 (hgnc:15459). hgnc:15459 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (7 references)
PMID:23345450 SUPPORT Human Clinical
"Here we used genetics and functional studies to show that a shared cause of these disorders may be loss of function of the ATP-gated P2X(2) receptor (ligand-gated ion channel, purinergic receptor 2) that is expressed in sensory and supporting cells of the cochlea."
The gene-disease relationship and the cell types in which the receptor acts.
PMID:24211385 SUPPORT Human Clinical
"The identification of a second most likely causative mutation in P2RX2 gene further supports the possible role of this gene in causing autosomal dominant HHL."
The first independent replication, and its hedged wording is preserved because at that point the gene rested on two families.
PMID:25788561 SUPPORT Human Clinical
"Two patients carried the mutation and had severe sensorineural hearing loss, while other members with MELAS (who did not carry the P2RX2 mutation) had normal hearing."
Reads as a clean natural experiment within a family segregating the MELAS 3243A>G variant, with hearing loss tracking the P2RX2 allele rather than the mitochondrial one. Graded PARTIAL rather than SUPPORT because ClinGen's Hearing Loss expert panel reviewed this family and did not accept it, on the grounds that the evidence for pathogenicity was not strong and the variant is present in gnomAD. Curated with that disagreement visible rather than silently dropped or silently believed.
+ 4 more references
💊

Medical Actions

3
Hearing Conservation and Noise Avoidance
The one intervention that follows directly from the mechanism. A DFNA41 carrier has lost the purinergic adaptation that limits cochlear amplifier gain under loud sound, so the ordinary advice about hearing protection carries more weight for them than for the general population. Noise exposure has been shown to exacerbate high-frequency hearing loss in carriers, and in the allele-matched mouse the noise hypersensitivity is a distinct, separately rescuable phenotype. This is behavioural rather than pharmacological, and no trial has tested whether noise avoidance changes the trajectory in carriers - the recommendation is inferred from the exposure-outcome association and from the mechanism, not from an intervention study.
Show evidence (2 references)
PMID:23345450 SUPPORT Human Clinical
"Similarly, among family members heterozygous for P2RX2 p.V60L, noise exposure exacerbated high-frequency hearing loss in young adulthood."
Graded PARTIAL because it establishes the exposure-outcome association that motivates avoidance, not that avoidance improves outcomes; no interventional evidence exists.
PMID:23345450 SUPPORT Human Clinical
"Our results suggest that P2X(2) function is required for life-long normal hearing and for protection from exposure to noise."
The protective role whose loss is the rationale for conservation advice.
Genetic Counselling with Audiologic Surveillance
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Counselling for a fully penetrant dominant condition with a 50 percent transmission risk, and serial audiometry in at-risk relatives. Onset between 25 and 35 years means a normal audiogram in a young adult relative is not reassurance, and it also means there is a long presymptomatic window in which noise conservation could in principle matter most.
Show evidence (2 references)
PMID:23345450 SUPPORT Human Clinical
"which cosegregated with fully penetrant hearing loss in the index family"
Full penetrance, which is what makes the transmission risk counselling definite.
PMID:31593348 SUPPORT Human Clinical
"The onset of hearing loss was between age 25 and 35 years."
The onset window that determines when surveillance of an at-risk relative becomes informative.
Cochlear Implantation
Action: cochlear implantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cochlear implantation, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Implantation for an ear that has reached profound loss. The reported DFNA41 experience is a single proband from a five-generation Chinese kindred carrying p.Val60Leu, with a satisfactory outcome. That family is also the one with earlier onset and worse hearing than the original DFNA41 families, so it is the part of the phenotypic range where implantation becomes relevant.
Show evidence (1 reference)
PMID:39258340 SUPPORT Human Clinical
"The cochlear implant (CI) was also provided for the proband of profound deafness, resulting in satisfactory clinical outcomes."
The implantation and its outcome in a molecularly confirmed DFNA41 proband.
🌍

Environmental Factors

1
Occupational and recreational noise exposure
exposure to sound radiation ECTO:8000044 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to sound radiation (ECTO:8000044). ECTO:8000044 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Exposure to elevated sound levels, which in DFNA41 is not a separate risk factor layered on top of the genetic disease but an interaction with the exact mechanism the disease disables. P2X2-mediated purinergic adaptation is what normally limits cochlear amplifier gain as sound levels rise; a carrier has less of that protection, so the same exposure does more damage.
Show evidence (2 references)
PMID:23345450 SUPPORT Human Clinical
"Similarly, among family members heterozygous for P2RX2 p.V60L, noise exposure exacerbated high-frequency hearing loss in young adulthood."
The human evidence that noise exposure modifies the phenotype in carriers, which is what justifies curating it as an environmental entry at all.
PMID:23345450 SUPPORT Human Clinical
"Our results suggest that P2X(2) function is required for life-long normal hearing and for protection from exposure to noise."
The authors' framing of P2X2 as protective against noise, stated for the human gene.
Mechanism Target:
EXACERBATES Noise-Exacerbated High-Frequency Hearing Impairment — Noise exposure worsens and brings forward the high-frequency component of DFNA41 hearing loss in carriers. The effect is on the phenotype rather than on the genetic lesion, which is why the edge lands here rather than on the channel node.
Show evidence (2 references)
PMID:23345450 SUPPORT Human Clinical
"Similarly, among family members heterozygous for P2RX2 p.V60L, noise exposure exacerbated high-frequency hearing loss in young adulthood."
Direct human evidence for exposure exacerbating this specific phenotype.
PMID:23345450 SUPPORT Model Organism
"P2RX2-null mice developed severe progressive hearing loss, and their early exposure to continuous moderate noise led to high-frequency hearing loss as young adults."
The controlled-exposure counterpart in mice, where the noise history is known rather than recalled.
MODULATES Loss of Purinergic Adaptation to Elevated Sound Levels — Sound level is the input to the adaptation system, not merely a hazard acting on it. Elevated sound is what drives ATP release and P2X2 activation in the first place, so the node has no output at all without this exposure - which is why a carrier is indistinguishable from a non-carrier on this axis in quiet conditions and diverges under noise. Recorded as MODULATES rather than EXACERBATES because sound is the physiological stimulus for the mechanism rather than an aggravating agent applied to it.
Show evidence (2 references)
PMID:23592720 SUPPORT Model Organism
"ATP released from the tissues of the cochlear partition with elevation of sound levels likely activates the broadly distributed P2X2 receptors on epithelial cells lining the endolymphatic compartment."
Sound level as the input that drives the purinergic signal.
PMID:23592720 SUPPORT Model Organism
"In mice null for the P2RX2 gene (encoding the P2X2 receptor subunit), sustained 85-dB noise failed to elicit the TTS that wild-type (WT) mice developed."
The divergence appears only under noise, which is the operational meaning of sound level modulating this node.
🔬

Diagnosis

1
Take a noise history, and do not let it explain the audiogram away
The diagnostic trap in DFNA41 is that its phenotype resembles the two commonest acquired causes of adult sensorineural hearing loss. Onset at 25 to 35 years with progressive high-frequency loss in someone with an occupational or recreational noise history looks like noise-induced hearing loss, and later it looks like early presbycusis. A dominant family history is the signal that should prompt sequencing. The noise history still matters, but as a modifier rather than as an alternative explanation: in a carrier, noise exposure and the genetic defect are the same story, because the gene encodes the protection against the noise. Diagnosis is by gene panel or exome sequencing; P2RX2 has been found through targeted enrichment panels of known nonsyndromic hearing loss genes.
Show evidence (2 references)
PMID:31593348 SUPPORT Human Clinical
"Our study and the review of the literature suggest that P2RX2 plays a crucial role in predisposition to noise-induced and age-related hearing loss."
The overlap with the two acquired causes that DFNA41 is most likely to be misattributed to.
PMID:25788561 SUPPORT Human Clinical
"Targeted genomic enrichment and massively parallel sequencing of all known nonsyndromic hearing loss genes were performed to identify the genetic causes of hearing loss."
The diagnostic route by which a P2RX2 family was found, and a reminder that a coexisting explanation for deafness in the family did not preclude a second one.
📊

Prevalence

1
Worldwide, published cases
Cases In Literature Ultra Rare
A small number of families: the founding six-generation kindred plus a second family with the same p.Val60Leu allele, an Italian family with p.Gly353Arg, a Japanese family with p.Asp201Tyr identified in a 194-family series, and an Iranian family with a stop-loss allele. No population prevalence estimate exists.
Show evidence (1 reference)
PMID:25788561 SUPPORT Human Clinical
"One hundred ninety-four (194) Japanese subjects from unrelated families were enrolled in the study."
The denominator of the series in which one P2RX2 family was found, which is the only quantitative handle on how uncommon this gene is among hearing loss families.
🧫

Experimental Models

1
Patient-derived P2RX2 p.Val60Leu hiPSC lines and their CRISPR homozygous isogenic control IPSC_DERIVED_MODEL
The only human-genetic-background model of DFNA41. Patient hiPSCs carry the causal allele in the patients' own genome, and CRISPR/Cas9 with single-stranded donor oligonucleotides converted them to a homozygous isogenic line, so allele dosage can be varied against a fixed background. What this paper reports is the construction of the lines, not a phenotype measured in them. There is no differentiation to otic or hair-cell fate, no electrophysiology, and no functional comparison between the heterozygous and homozygous lines - so the entry records the model as a resource that manipulates the channel defect, not as one that reproduces any consequence of it.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
Non-integrative hiPSCs reprogrammed from urine-derived epithelial cells of three members of a large Chinese kindred heterozygous for P2RX2 c.178G>T (p.Val60Leu).
Publication
PMID:30819013
Pathograph links
P2X2 Receptor Loss of Function perturbs fidelity: unknown Establishes the p.Val60Leu allele at two dosages in a human genetic background: the patients' own heterozygous state, and an engineered homozygote as a control for gene function.
Limitations: Fidelity is UNKNOWN rather than graded because nothing about the channel or its downstream consequences was measured in these cells. Undifferentiated iPSCs are not hair cells and do not express the cochlear context in which P2X2 matters, and the homozygous line is an engineered dosage control with no human counterpart - DFNA41 is dominant and no homozygous patient has been reported.
Show evidence (1 reference)
PMID:30819013 SUPPORT In Vitro
"we used CRISPR/Cas9 and single-stranded donor oligonucleotides to genetically establish homozygous P2RX2 c.178G>T hiPSCs (designated P2RX2-/-) from heterozygous patient-specific hiPSCs as a control to further study the pathological gene function."
The editing step that makes this a dosage series for the node rather than a single patient line.
Curated as an experimental_models entry rather than an animal_models one because hiPSCs are a non-animal system, and with no readouts because the publication reports none. It is included despite that: it is the only DFNA41 model in a human genetic background, and its absence would leave the entry looking as though the disease has only mouse and zebrafish models.
Show evidence (2 references)
PMID:30819013 SUPPORT In Vitro
"We generated non-integrative hiPSCs from urine samples derived from three members of a large Chinese family carrying heterozygous P2RX2 c.178G>T mutations (designated P2RX2+/-) as a model to study P2RX2-mediated hereditary HL."
The derivation of the patient lines and the allele they carry.
PMID:30819013 SUPPORT In Vitro
"Heterozygous and homozygous P2RX2-mutated hiPSC lines are good models to investigate the pathological mechanisms of P2RX2 mutations in HL pathogenesis."
Graded PARTIAL because it is a claim about future utility, not a result: the authors say the lines are good models to investigate mechanisms, having investigated none.
🐁

Animal Models

4
P2rx2 V60L knock-in mouse
An allele-matched model of the human founding variant, and the one that makes DFNA41 unusually well served among dominant deafness loci - the mouse carries the same substitution as the patients rather than a null. Heterozygotes begin to lose hearing at 21 days and are deaf by six months, with progressive abnormality of inner hair cell and ribbon synapse morphology, and vestibular dysfunction.
Species
Mouse
Genotype
P2rx2 V60L knock-in, heterozygous
Genes
P2RX2 hgnc:15459 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns P2RX2 (hgnc:15459). hgnc:15459 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:33791800
Pathograph links
Inner Hair Cell and Ribbon Synapse Disorganisation recapitulates fidelity: high The only system in which inner hair cell and ribbon synapse morphology has been examined for this disease - no human DFNA41 temporal bone study exists, and the zebrafish and null-mouse work reports neither. It is allele-matched and heterozygous, so it reproduces the human genetic state rather than approximating it with a null.
Limitations: The time course is compressed to an extent that changes its meaning: mice are deaf by six months, while patients begin to lose hearing at 25 to 35 years and decline over decades. A phenotype that in mice looks like early-onset progressive deafness is in humans an adult-onset one. Synapse morphology has also not been examined in any human DFNA41 temporal bone, so the correspondence is assumed rather than checked. The vestibular dysfunction seen in these mice has no curated human counterpart: no vestibular testing is reported for any molecularly confirmed DFNA41 carrier, so it stays a model finding here rather than becoming a disease phenotype.
Readouts
Inner hair cell and ribbon synapse morphology
Direction: ALTERED
Interpretation: Progressive morphological abnormality rather than an all-or-none defect, appearing over the same period as the hearing decline.
Show evidence (1 reference)
PMID:33791800 SUPPORT Model Organism
"Abnormal morphology of the inner hair cells and ribbon synapses was progressively observed in KI animals suggesting that P2rx2 plays a role in the membrane spatial location of the ribbon synapses."
The structural measurement behind this readout.
Auditory function over time
Direction: DECREASED
Interpretation: Progressive hearing loss from 21 days to deafness by six months. The readout is named for function rather than for threshold because the cited sentence reports hearing loss, and a threshold moves in the opposite direction to the function it measures.
Show evidence (1 reference)
PMID:33791800 SUPPORT Model Organism
"Heterozygous KI mice started to exhibit hearing loss at 21-day-old and progressed to deafness by 6-month-old."
The functional time course in the allele-matched heterozygote.
Show evidence (1 reference)
PMID:33791800 SUPPORT Model Organism
"We generated and characterized a knock-in mouse model based on human p.V60L mutation that recapitulates the human phenotype."
The authors' claim of recapitulation, on the same allele as the patients.
P2rx2 null mouse
The model in which the purinergic adaptation mechanism was established. Nulls lack ATP-gated conductance across the cochlear partition including ATP-gated inward current in hair cells, fail to develop the temporary threshold shift that wild-type mice develop under sustained 85 dB noise, and are more vulnerable than wild-type mice to permanent loss at 95 dB and above.
Species
Mouse
Genotype
P2rx2 null, homozygous
Genes
P2RX2 hgnc:15459 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns P2RX2 (hgnc:15459). hgnc:15459 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:23592720
Pathograph links
Loss of Purinergic Adaptation to Elevated Sound Levels recapitulates fidelity: moderate Defines the mechanism, with the conductance measurement, the behavioural threshold measurement and the supporting emission and gain data all in one system. Nothing equivalent can be measured in patients.
Limitations: A homozygous null against a human heterozygous state, so it models complete loss of the mechanism rather than the partial loss a carrier has - and partial is the clinically relevant condition, since the dominant allele degrades but does not abolish the function of channels containing wild-type subunits. Sound levels and exposure schedules are also experimental rather than matched to any human exposure history.
Readouts
Noise-induced temporary threshold shift
Direction: ABOLISHED
Interpretation: The adaptive response to moderate sustained noise does not occur in the absence of P2X2. This is the defining measurement of the node.
Show evidence (1 reference)
PMID:23592720 SUPPORT Model Organism
"In mice null for the P2RX2 gene (encoding the P2X2 receptor subunit), sustained 85-dB noise failed to elicit the TTS that wild-type (WT) mice developed."
The threshold-shift measurement in the null.
ATP-gated conductance across the cochlear partition
Direction: ABOLISHED
Interpretation: The electrophysiological substrate of the adaptation is absent, which is what makes the behavioural result mechanistic rather than merely correlated.
Show evidence (1 reference)
PMID:23592720 SUPPORT Model Organism
"P2RX2-null mice lacked ATP-gated conductance across the cochlear partition, including loss of ATP-gated inward current in hair cells."
The direct conductance measurement in the null.
Show evidence (1 reference)
PMID:23592720 SUPPORT Model Organism
"These data indicate that a significant component of TTS represents P2X2 receptor-dependent purinergic hearing adaptation that underpins the upper physiological range of hearing."
The conclusion this node curates, drawn from this model.
P2rx2 V61L knock-in mouse treated with AAV-delivered SaCas9
Allele-specific genome editing in the mature inner ear of the knock-in heterozygote. Local injection produced efficient and specific editing that abolished the mutation without notable off-target effects or AAV genome integration, restored long-term auditory and vestibular function, and protected the animals from noise hypersensitivity. Intervention at a juvenile stage broadened the frequency range rescued. A gRNA effective against the human V60L allele was also identified.
Species
Mouse
Genotype
P2rx2 V61L/+ knock-in treated with AAV2 SaCas9-sgRNA targeting the mutant allele
Genes
P2RX2 hgnc:15459 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns P2RX2 (hgnc:15459). hgnc:15459 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:41090360
Pathograph links
Loss of Purinergic Adaptation to Elevated Sound Levels rescues fidelity: moderate The forward test of the mechanism. Removing the mutant allele restores not just hearing but specifically the resistance to noise, which is the functional signature of the purinergic adaptation this entry places at the centre of the disease. That the noise phenotype rescues separately is the strongest available evidence that it is mechanistically distinct from the baseline progressive loss rather than a consequence of it.
Limitations: Editing removes the dominant allele in a mouse whose own P2rx2 numbering differs (V61L against human V60L) and whose disease runs its course in months rather than decades, so the treated window has no clear human equivalent. The authors show that juvenile intervention broadens the rescued frequency range, which implies that later treatment does less - and human DFNA41 is not diagnosable until adulthood, well past any comparable stage. The human gRNA was identified, not tested in patients.
Readouts
Resistance to noise-induced hearing loss after editing
Direction: RESTORED
Interpretation: Protection against noise is restored, not merely baseline hearing, which maps the rescue onto the adaptation mechanism specifically. Named for resistance rather than susceptibility so that RESTORED reads in the same direction as the measure.
Show evidence (1 reference)
PMID:41090360 SUPPORT Model Organism
"Editing further protects P2rx2V61L/+ mice from hypersensitivity to noise-induced hearing loss, a phenotype also observed in patients with DFNA41."
The noise-specific rescue, and the authors' own statement that the phenotype rescued is one patients have.
Auditory and vestibular function after editing
Direction: RESTORED
Interpretation: Long-term restoration of both systems from a single dose.
Show evidence (1 reference)
PMID:41090360 SUPPORT Model Organism
"Editing effectively restores long-term auditory and vestibular function."
The primary functional outcome of the intervention.
Show evidence (1 reference)
PMID:41090360 SUPPORT Model Organism
"We demonstrate that local injection in adult mice results in efficient and specific editing that abolishes the mutation without notable off-target effects or AAV genome integration."
Establishes that the intervention did what it was supposed to at the molecular level, which is what licenses reading the functional rescue as mechanism-specific.
Show evidence (1 reference)
PMID:41090360 SUPPORT Model Organism
"Intervention in mice at a juvenile stage broadens the frequency range rescued, highlighting the importance of early intervention."
Graded PARTIAL because it qualifies the rescue rather than supporting it: the benefit is timing-dependent, and the timing that works best has no counterpart in a disease diagnosed in adults.
p2rx2 knockout zebrafish
A CRISPR/Cas9 loss-of-function line in the P2RX2 orthologue, and the only non-mammalian model of this gene's auditory role. Homozygous mutants develop normally but lose hair cell density in the otolith region - the zebrafish saccule, which is the auditory organ - while lateral line neuromasts are spared, and their auditory evoked potential thresholds are raised at every frequency tested.
Species
Zebrafish
Genotype
p2rx2 knockout (66 bp insertion introducing a premature TAA), homozygous
Genes
P2RX2 hgnc:15459 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns P2RX2 (hgnc:15459). hgnc:15459 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:41015553
{ }

Source YAML

click to show 
name: Autosomal Dominant Nonsyndromic Hearing Loss 41
category: Mendelian
creation_date: "2026-08-28T00:00:00Z"
synonyms:
- DFNA41
- deafness, autosomal dominant 41
- P2RX2 autosomal dominant nonsyndromic deafness
- autosomal dominant nonsyndromic deafness caused by mutation in P2RX2
- autosomal dominant nonsyndromic deafness type 41
- deafness, autosomal dominant type 41
- autosomal dominant deafness 41
- autosomal dominant nonsyndromic deafness 41
description: >-
  DFNA41 is dominantly inherited, delayed-onset, progressive sensorineural hearing loss
  caused by heterozygous variants in P2RX2, which encodes the P2X2 subunit of an
  ATP-gated cation channel expressed on sensory and supporting cells of the cochlea.
  Onset in the original six-generation kindred was between 25 and 35 years, and hearing
  loss was fully penetrant and involved all frequencies.

  The reason to curate this entry rather than treat it as one more dominant deafness locus
  is that P2X2 is not a structural protein of the hair bundle. It is part of a feedback
  system. Rising sound levels cause ATP release into the endolymphatic compartment, ATP
  opens P2X2 channels on the epithelium lining that compartment, and the resulting
  conductance turns down the gain of the cochlear amplifier. That is what a temporary
  threshold shift is: not damage, but a protective adaptation to loud sound. P2RX2-null
  mice do not develop the temporary threshold shift that wild-type mice develop under
  sustained 85 dB noise, and at higher levels they sustain more permanent damage than
  wild-type mice do.

  So DFNA41 is a disorder of a protective mechanism, and its clinical signature follows
  from that. Hearing declines on its own, but noise exposure makes it worse, and this has
  been observed on both sides of the same experiment: P2RX2-null mice exposed early to
  continuous moderate noise had high-frequency hearing loss as young adults, and among
  heterozygous family members carrying p.Val60Leu, noise exposure exacerbated
  high-frequency hearing loss in young adulthood. The environmental interaction is
  therefore modelled here as a pathograph edge rather than left as prose, because for this
  disease it is a mechanism rather than a lifestyle note.

  The molecular defect for the founding allele is well characterised. P2RX2 p.Val60Leu
  abolishes both hallmark properties of the receptor, the ATP-evoked inward current and
  the ATP-stimulated macropore permeability, and coexpressing mutant with wild-type
  subunits significantly reduces ATP-activated membrane permeability - which is what makes
  a heterozygous allele dominant in a channel assembled from three subunits.

  There is a genome-editing proof of concept. AAV-delivered SaCas9 disrupting the mutant
  allele in the mature inner ear of a knock-in mouse restored auditory and vestibular
  function long-term, and specifically protected against noise hypersensitivity, which
  says the environmental arm of this disease is itself addressable rather than only its
  baseline hearing loss. The authors frame the novelty as extending editing beyond hearing
  rescue; whether it is the first such demonstration is their claim to make, not this
  entry's.
  Intervention at a juvenile stage widened the frequency range rescued.

  One recent finding unsettles the "nonsyndromic" label. A five-generation Chinese kindred
  carrying the same p.Val60Leu allele was tested for pain perception quantitatively, and
  heterozygotes showed hyperalgesia. P2X2 receptors sit on sensory neurons and purinergic
  signalling has an established role in nociception, so this is not a surprising place for
  the channel to matter - but no earlier DFNA41 report looked for it, so how general it is
  cannot be stated. That family also had earlier onset and worse hearing than the original
  ones on the same allele, which is a reminder that the 25-to-35-year window is a property
  of the founding kindred rather than of the variant.
disease_term:
  preferred_term: autosomal dominant nonsyndromic hearing loss 41
  term:
    id: MONDO:0011994
    label: autosomal dominant nonsyndromic hearing loss 41
parents:
- Autosomal Dominant Nonsyndromic Hearing Loss
inheritance:
- name: Autosomal dominant
  description: >-
    Heterozygous P2RX2 variants, fully penetrant in the founding six-generation kindred.
    Dominance is mechanistically accounted for rather than merely observed: P2X2 receptors
    are trimeric, so a mutant subunit incorporated into a heteromeric channel reduces the
    function of the whole assembly, and this was measured directly in coexpression
    experiments.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:23345450
    reference_title: "Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genomic analysis of dominantly inherited, progressive sensorineural hearing loss DFNA41 in a six-generation kindred revealed a rare heterozygous allele, P2RX2 c.178G > T (p.V60L), at chr12:133,196,029, which cosegregated with fully penetrant hearing loss in the index family, and also appeared in a second family with the same phenotype."
    explanation: The founding pedigree, the allele, and full penetrance in two families.
  - reference: PMID:23345450
    reference_title: "Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Coexpression of mutant and WT P2X(2) receptor subunits significantly reduced ATP-activated membrane permeability."
    explanation: >-
      The mechanistic basis of dominance in a multimeric channel, measured rather than
      assumed.
  - reference: PMID:24211385
    reference_title: "A novel P2RX2 mutation in an Italian family affected by autosomal dominant nonsyndromic hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We performed a linkage analysis in a large Italian family with a dominant pattern of inheritance showing a significant 3.31 LOD score in a 2Mb region overlapping with the DNFA41 locus."
    explanation: Independent linkage evidence for dominant inheritance at the same locus.
pathophysiology:
- name: P2X2 Receptor Loss of Function
  description: >-
    Heterozygous P2RX2 alleles that cripple the ATP-gated channel. The best-characterised
    is p.Val60Leu, which abolishes both defining properties of P2X2 receptors: the
    ATP-evoked inward current and the ATP-stimulated macropore permeability measured as
    loss of ATP-activated FM1-43 labelling. Other reported alleles are p.Gly353Arg in an
    Italian family, predicted by comparative modelling to destabilise the fold near the
    region controlling channel gating, p.Asp201Tyr in a Japanese family, and a stop-loss
    variant p.Ter350Glu in an Iranian family that would extend translation into the
    3-prime untranslated region and yield a longer protein.

    The dominant mechanism is subunit poisoning rather than simple haploinsufficiency.
    P2X2 channels assemble from three subunits, and coexpressing mutant with wild-type
    subunits significantly reduced ATP-activated permeability, so a single mutant allele
    degrades the function of channels that also contain wild-type subunits.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: P2RX2
    term:
      id: hgnc:15459
      label: P2RX2
  genetic_context:
    gene:
      preferred_term: P2RX2
      term:
        id: hgnc:15459
        label: P2RX2
    allele_type: SNV
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: DOMINANT_NEGATIVE
    description: >-
      Heterozygous germline missense and stop-loss alleles. Recorded as DOMINANT_NEGATIVE
      rather than LOSS_OF_FUNCTION because the mutant subunit does not merely fail: it is
      incorporated into a trimeric channel alongside wild-type subunits and degrades that
      channel's function, which was measured directly in coexpression and is the reading
      ClinGen's Hearing Loss Gene Curation Expert Panel also takes.
  molecular_functions:
  - preferred_term: extracellularly ATP-gated monoatomic cation channel activity
    term:
      id: GO:0004931
      label: extracellularly ATP-gated monoatomic cation channel activity
    modifier: DECREASED
  downstream:
  - target: Loss of Purinergic Adaptation to Elevated Sound Levels
    causal_link_type: DIRECT
  - target: Inner Hair Cell and Ribbon Synapse Disorganisation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:23345450
    reference_title: "Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "P2RX2 p.V60L abolishes two hallmark features of P2X(2) receptors: ATP-evoked inward current response and ATP-stimulated macropore permeability, measured as loss of ATP-activated FM1-43 fluorescence labeling."
    explanation: The direct electrophysiological and permeability measurement of the founding allele.
  - reference: PMID:23345450
    reference_title: "Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mutation was absent from more than 7,000 controls."
    explanation: Population-frequency evidence supporting pathogenicity of the founding allele.
  - reference: PMID:24211385
    reference_title: "A novel P2RX2 mutation in an Italian family affected by autosomal dominant nonsyndromic hearing loss."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Visual inspection of the protein structure as obtained from comparative modeling suggests that substitution of the small glycine residue with a charged bulky residue such as an arginine that is close to the 'neck' of the region responsible for ion channel gating should have a high energetic cost and should lead to a severely destabilization of the fold."
    explanation: >-
      The structural rationale for the second reported allele. Graded COMPUTATIONAL because
      it is comparative modelling, not a functional assay.
  - reference: PMID:34425661
    reference_title: "Identification of a Novel Stop Loss Mutation in P2RX2 Gene in an Iranian Family with Autosomal Nonsyndromic Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This event would lead to continued translation into the 3' UTR of the gene, which in turn may result in a longer protein product."
    explanation: >-
      A mechanistically distinct allele class - stop loss producing an extended protein
      rather than a substitution - which is why the entry describes the spectrum by
      consequence rather than by variant type.
- name: Loss of Purinergic Adaptation to Elevated Sound Levels
  description: >-
    The core mechanism, and the one that makes DFNA41 unlike the structural deafness genes.
    As sound level rises, ATP is released from the tissues of the cochlear partition and
    activates P2X2 receptors distributed on the epithelial cells lining the endolymphatic
    compartment. The resulting conductance reduces the gain of the cochlear amplifier,
    which appears in auditory brainstem responses as a temporary threshold shift. This is
    an adaptive response to loud sound rather than injury.

    P2RX2-null mice do not develop that shift under sustained 85 dB noise, and the
    supporting measurements show the failure is upstream in the intended place: outer hair
    cell distortion product emissions are suppressed by noise significantly more in
    wild-type than in null mice, and suprathreshold response gain falls more in wild-type
    animals. Losing the adaptation is not protective; it removes a brake. At 95 dB and
    above the nulls are more vulnerable than wild-type mice to permanent hearing loss
    through hair cell synapse disruption.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: cochlear outer hair cell
    term:
      id: CL:0000601
      label: cochlear outer hair cell
  - preferred_term: supporting cell
    term:
      id: CL:0000630
      label: supporting cell
  biological_processes:
  - preferred_term: purinergic nucleotide receptor signaling pathway
    term:
      id: GO:0035590
      label: purinergic nucleotide receptor signaling pathway
    modifier: DECREASED
  downstream:
  - target: Inner Hair Cell and Ribbon Synapse Disorganisation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Noise-Exacerbated High-Frequency Hearing Impairment
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:23592720
    reference_title: "ATP-gated ion channels mediate adaptation to elevated sound levels."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We show that ATP-gated ion channels assembled from P2X2 receptor subunits in the cochlea are necessary for the development of temporary threshold shift (TTS), evident in auditory brainstem response recordings as sound levels rise."
    explanation: The central claim of this node, established in the null mouse.
  - reference: PMID:23592720
    reference_title: "ATP-gated ion channels mediate adaptation to elevated sound levels."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In mice null for the P2RX2 gene (encoding the P2X2 receptor subunit), sustained 85-dB noise failed to elicit the TTS that wild-type (WT) mice developed."
    explanation: The specific loss-of-adaptation result at a moderate, non-damaging sound level.
  - reference: PMID:23592720
    reference_title: "ATP-gated ion channels mediate adaptation to elevated sound levels."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "ATP released from the tissues of the cochlear partition with elevation of sound levels likely activates the broadly distributed P2X2 receptors on epithelial cells lining the endolymphatic compartment."
    explanation: >-
      The proposed signalling route. Recorded with the authors' own hedge intact, since
      the release step is inferred rather than directly imaged.
  - reference: PMID:23592720
    reference_title: "ATP-gated ion channels mediate adaptation to elevated sound levels."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "At higher sound levels (≥95 dB), additional processes dominated TTS, and P2RX2-null mice were more vulnerable than WT mice to permanent hearing loss due to hair cell synapse disruption."
    explanation: >-
      The consequence of losing the brake, and the link from this node to the synaptic one:
      above the adaptive range, absence of P2X2 converts a survivable exposure into
      permanent loss.
  - reference: PMID:23592720
    reference_title: "ATP-gated ion channels mediate adaptation to elevated sound levels."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These data indicate that a significant component of TTS represents P2X2 receptor-dependent purinergic hearing adaptation that underpins the upper physiological range of hearing."
    explanation: >-
      The reframing this entry depends on: temporary threshold shift as physiology rather
      than as early damage.
- name: Inner Hair Cell and Ribbon Synapse Disorganisation
  description: >-
    The structural correlate seen in the knock-in mouse carrying the human founding allele.
    Abnormal inner hair cell and ribbon synapse morphology appears progressively, which the
    authors read as P2rx2 having a role in where ribbon synapses sit in the membrane. This
    is consistent with the finding in null mice that above the adaptive range, permanent
    loss occurs through hair cell synapse disruption.

    The node is drawn with an unknown-intermediate link from the channel defect because
    nothing connects loss of ATP-gated conductance to synaptic placement mechanistically;
    the two are observed in the same animals, not shown to be steps in one chain.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: cochlear inner hair cell
    term:
      id: CL:0000589
      label: cochlear inner hair cell
  downstream:
  - target: Progressive Sensorineural Hearing Impairment
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:33791800
    reference_title: "Generation and characterization of a P2rx2 V60L mouse model for DFNA41."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Abnormal morphology of the inner hair cells and ribbon synapses was progressively observed in KI animals suggesting that P2rx2 plays a role in the membrane spatial location of the ribbon synapses."
    explanation: >-
      The structural finding in the allele-matched knock-in, stated with the authors'
      hedge about what it suggests.
  - reference: PMID:23592720
    reference_title: "ATP-gated ion channels mediate adaptation to elevated sound levels."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "At higher sound levels (≥95 dB), additional processes dominated TTS, and P2RX2-null mice were more vulnerable than WT mice to permanent hearing loss due to hair cell synapse disruption."
    explanation: >-
      Graded PARTIAL because it attributes permanent noise damage in nulls to synapse
      disruption without measuring synapse morphology; it corroborates the knock-in
      finding rather than independently establishing it.
phenotypes:
- name: Progressive Sensorineural Hearing Impairment
  category: Auditory
  description: >-
    Bilateral sensorineural hearing loss involving all frequencies, worsening over
    decades, confirmed both by history and by audiological follow-up in the original
    kindred at ten-year review.
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Progressive sensorineural hearing impairment
    term:
      id: HP:0000408
      label: Progressive sensorineural hearing impairment
  evidence:
  - reference: PMID:31593348
    reference_title: "Progressive Dominant Hearing Loss (Autosomal Dominant Deafness-41) and P2RX2 Gene Mutations: A Phenotype-Genotype Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Progressive hearing impairment was confirmed by history and by audiological follow-up testing in all the patients."
    explanation: >-
      Progression established prospectively rather than by recall, in a ten-year follow-up
      of the founding family.
  - reference: PMID:31593348
    reference_title: "Progressive Dominant Hearing Loss (Autosomal Dominant Deafness-41) and P2RX2 Gene Mutations: A Phenotype-Genotype Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All affected subjects had bilateral sensorineural hearing loss involving all frequencies with some significant gender differences."
    explanation: Bilaterality and the all-frequency configuration in the same cohort.
- name: Adult-Onset Hearing Impairment
  category: Auditory
  description: >-
    Onset in the founding kindred was between 25 and 35 years - late enough that affected
    individuals have normal hearing through childhood and into early adult life, and late
    enough that the disease can be mistaken for early presbycusis or for occupational
    noise damage in someone with a noise history.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Adult-onset sensorineural hearing impairment
    term:
      id: HP:0008615
      label: Adult onset sensorineural hearing impairment
  evidence:
  - reference: PMID:31593348
    reference_title: "Progressive Dominant Hearing Loss (Autosomal Dominant Deafness-41) and P2RX2 Gene Mutations: A Phenotype-Genotype Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The onset of hearing loss was between age 25 and 35 years."
    explanation: The age-at-onset range in the best-characterised family.
  - reference: PMID:39258340
    reference_title: "Novel Clinical Manifestation and Favorable Treatment Outcome of Cochlear Implant in a Chinese Family With Likely Pathogenic Variant of the P2RX2 Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite carrying the same variant, the affected members in this family appear to present with earlier-onset hearing loss and poorer hearing compared to the original DFNA41 families."
    explanation: >-
      Graded PARTIAL because it qualifies the onset window rather than confirming it. A
      later five-generation Chinese kindred carrying the same p.Val60Leu allele had earlier
      onset and worse hearing than the original families, so the 25-to-35-year range is not
      a property of the allele.
  notes: >-
    The 25-to-35-year window is the RESULTS statement of PMID:31593348, the ten-year
    follow-up of the founding kindred. Yan 2013 (PMID:23345450) reports a 12-to-20-year
    window for what is the same family, so the two published descriptions of one kindred
    disagree; the later, prospectively followed report is the one cited here.

    frequency is FREQUENT rather than VERY_FREQUENT for that reason. Adult onset is not
    established in 80 to 99 percent of carriers: one published reading of the founding
    kindred puts onset in adolescence, and the Chinese p.Val60Leu family had onset earlier
    still. What is uncontested across every report is postlingual onset, which is curated
    separately and graded OBLIGATE; adulthood specifically is the part the sources
    disagree about.
- name: Bilateral Sensorineural Hearing Impairment
  category: Auditory
  description: >-
    Both ears are affected in every subject of the ten-year follow-up of the founding
    kindred, which is the only DFNA41 series with systematic audiological review.
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Bilateral sensorineural hearing impairment
    term:
      id: HP:0008619
      label: Bilateral sensorineural hearing impairment
  evidence:
  - reference: PMID:31593348
    reference_title: "Progressive Dominant Hearing Loss (Autosomal Dominant Deafness-41) and P2RX2 Gene Mutations: A Phenotype-Genotype Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All affected subjects had bilateral sensorineural hearing loss involving all frequencies with some significant gender differences."
    explanation: >-
      Bilateral involvement in all affected subjects of the prospectively followed
      kindred, which is what makes OBLIGATE rather than a lower band the right grade.
- name: Noise-Exacerbated High-Frequency Hearing Impairment
  category: Auditory
  description: >-
    High-frequency hearing loss that appears earlier and is worse in carriers who have had
    noise exposure. This is the clinically actionable feature of DFNA41 and it is
    supported symmetrically in mice and in people: null mice exposed early to continuous
    moderate noise had high-frequency loss as young adults, and among family members
    heterozygous for p.Val60Leu, noise exposure exacerbated high-frequency hearing loss in
    young adulthood.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: High-frequency sensorineural hearing impairment
    term:
      id: HP:0001757
      label: High-frequency sensorineural hearing impairment
  evidence:
  - reference: PMID:23345450
    reference_title: "Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Similarly, among family members heterozygous for P2RX2 p.V60L, noise exposure exacerbated high-frequency hearing loss in young adulthood."
    explanation: The human observation of the gene-environment interaction.
  - reference: PMID:23345450
    reference_title: "Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "P2RX2-null mice developed severe progressive hearing loss, and their early exposure to continuous moderate noise led to high-frequency hearing loss as young adults."
    explanation: >-
      The matching result in mice, where exposure could be controlled rather than
      recalled.
  notes: >-
    Frequency is FREQUENT rather than higher because it is conditional on exposure: the
    phenotype is reported in family members who had noise exposure, and no reported series
    quantifies what fraction of all carriers that is.
- name: Postlingual Sensorineural Hearing Impairment
  category: Auditory
  description: >-
    Hearing is normal through speech acquisition and the loss declares itself afterwards.
    This is uncontested across every DFNA41 report, including the ones that disagree about
    the decade in which onset occurs, and it is what separates DFNA41 clinically from the
    congenital nonsyndromic deafness genes.
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Postlingual sensorineural hearing impairment
    term:
      id: HP:0008596
      label: Postlingual sensorineural hearing impairment
  evidence:
  - reference: CGGV:assertion_c1dae6b6-4ed7-4c5a-ba4e-bcfaba026be8-2022-09-21T160000.000Z
    reference_title: "P2RX2 / nonsyndromic genetic hearing loss (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The hearing loss in these families had a postlingual onset, was progressive, and co-occurred with tinnitus in one family."
    explanation: >-
      The expert panel's summary across all four curated probands, which is the broadest
      statement of postlingual onset available. Graded OTHER because a ClinGen curation
      reads other people's cases rather than reporting its own.
- name: Tinnitus
  category: Auditory
  description: >-
    Ringing or other phantom sound accompanying the hearing loss. ClinGen's Hearing Loss
    expert panel, reviewing the four probands on which the P2RX2 gene-disease relationship
    rests, records tinnitus in one of the reported families.
  phenotype_term:
    preferred_term: Tinnitus
    term:
      id: HP:0000360
      label: Tinnitus
  evidence:
  - reference: CGGV:assertion_c1dae6b6-4ed7-4c5a-ba4e-bcfaba026be8-2022-09-21T160000.000Z
    reference_title: "P2RX2 / nonsyndromic genetic hearing loss (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The hearing loss in these families had a postlingual onset, was progressive, and co-occurred with tinnitus in one family."
    explanation: >-
      The expert-panel summary of the reported DFNA41 families, which is where the tinnitus
      is recorded. Graded OTHER because a ClinGen curation is an expert reading of other
      people's cases rather than a study reporting its own.
  notes: >-
    frequency is deliberately absent. The source says "in one family" out of the four
    probands curated, which is a count of families rather than of affected individuals, so
    there is no patient denominator to grade a FrequencyEnum band against.
- name: Hyperalgesia
  category: Neurologic
  description: >-
    Increased pain sensitivity, measured quantitatively rather than reported, in
    heterozygous carriers of P2RX2 p.Val60Leu in a five-generation Chinese kindred. This is
    the one finding that puts pressure on calling DFNA41 nonsyndromic, and it is
    mechanistically unsurprising: P2X2 receptors are widely expressed on sensory neurons
    and purinergic signalling has an established role in nociception, so a channel defect
    that removes a protective brake in the cochlea has an obvious candidate action outside
    it.

    It rests on one family and one instrument, and no earlier DFNA41 report tested pain
    perception at all, so its frequency across the disorder is unknown rather than low.
  phenotype_term:
    preferred_term: Hyperalgesia
    term:
      id: HP:0012534
      label: Dysesthesia
  evidence:
  - reference: PMID:39258340
    reference_title: "Novel Clinical Manifestation and Favorable Treatment Outcome of Cochlear Implant in a Chinese Family With Likely Pathogenic Variant of the P2RX2 Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We quantitatively evaluated the pain perception ability of some members using the Pain Vision PS-2100 system, and further found an interesting clinical manifestation, that is, hyperalgesia, in heterozygotes for P2RX2 p.V60L."
    explanation: >-
      The measurement and the genotype it was made in. Quantitative rather than
      symptom-report, which matters for a finding this easy to dismiss.
  notes: >-
    HPO has no separate term for hyperalgesia. HP:0012534 carries Hyperalgesia and
    Hyperpathia as exact synonyms and its definition names both, so the binding is the one
    HPO intends, but the canonical label is Dysesthesia and its text describes pain from a
    nonpainful stimulus, which is closer to allodynia. preferred_term carries the accurate
    finding.

    frequency is deliberately absent rather than set to a low band. Pain perception was
    measured in one family and no other DFNA41 report tested it, so there is no
    denominator to grade against, and FrequencyEnum has no value meaning "not established".
environmental:
- name: Occupational and recreational noise exposure
  description: >-
    Exposure to elevated sound levels, which in DFNA41 is not a separate risk factor
    layered on top of the genetic disease but an interaction with the exact mechanism the
    disease disables. P2X2-mediated purinergic adaptation is what normally limits cochlear
    amplifier gain as sound levels rise; a carrier has less of that protection, so the same
    exposure does more damage.
  exposure_term:
    preferred_term: exposure to sound radiation
    term:
      id: ECTO:8000044
      label: exposure to sound radiation
  evidence:
  - reference: PMID:23345450
    reference_title: "Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Similarly, among family members heterozygous for P2RX2 p.V60L, noise exposure exacerbated high-frequency hearing loss in young adulthood."
    explanation: >-
      The human evidence that noise exposure modifies the phenotype in carriers, which is
      what justifies curating it as an environmental entry at all.
  - reference: PMID:23345450
    reference_title: "Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our results suggest that P2X(2) function is required for life-long normal hearing and for protection from exposure to noise."
    explanation: The authors' framing of P2X2 as protective against noise, stated for the human gene.
  influences_mechanisms:
  - target: Noise-Exacerbated High-Frequency Hearing Impairment
    environmental_effect: EXACERBATES
    causal_link_type: DIRECT
    description: >-
      Noise exposure worsens and brings forward the high-frequency component of DFNA41
      hearing loss in carriers. The effect is on the phenotype rather than on the genetic
      lesion, which is why the edge lands here rather than on the channel node.
    evidence:
    - reference: PMID:23345450
      reference_title: "Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Similarly, among family members heterozygous for P2RX2 p.V60L, noise exposure exacerbated high-frequency hearing loss in young adulthood."
      explanation: Direct human evidence for exposure exacerbating this specific phenotype.
    - reference: PMID:23345450
      reference_title: "Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "P2RX2-null mice developed severe progressive hearing loss, and their early exposure to continuous moderate noise led to high-frequency hearing loss as young adults."
      explanation: >-
        The controlled-exposure counterpart in mice, where the noise history is known
        rather than recalled.
  - target: Loss of Purinergic Adaptation to Elevated Sound Levels
    environmental_effect: MODULATES
    causal_link_type: DIRECT
    description: >-
      Sound level is the input to the adaptation system, not merely a hazard acting on it.
      Elevated sound is what drives ATP release and P2X2 activation in the first place, so
      the node has no output at all without this exposure - which is why a carrier is
      indistinguishable from a non-carrier on this axis in quiet conditions and diverges
      under noise. Recorded as MODULATES rather than EXACERBATES because sound is the
      physiological stimulus for the mechanism rather than an aggravating agent applied to
      it.
    evidence:
    - reference: PMID:23592720
      reference_title: "ATP-gated ion channels mediate adaptation to elevated sound levels."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "ATP released from the tissues of the cochlear partition with elevation of sound levels likely activates the broadly distributed P2X2 receptors on epithelial cells lining the endolymphatic compartment."
      explanation: Sound level as the input that drives the purinergic signal.
    - reference: PMID:23592720
      reference_title: "ATP-gated ion channels mediate adaptation to elevated sound levels."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In mice null for the P2RX2 gene (encoding the P2X2 receptor subunit), sustained 85-dB noise failed to elicit the TTS that wild-type (WT) mice developed."
      explanation: >-
        The divergence appears only under noise, which is the operational meaning of sound
        level modulating this node.
prevalence:
- population: Worldwide, published cases
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    A small number of families: the founding six-generation kindred plus a second family
    with the same p.Val60Leu allele, an Italian family with p.Gly353Arg, a Japanese family
    with p.Asp201Tyr identified in a 194-family series, and an Iranian family with a
    stop-loss allele. No population prevalence estimate exists.
  evidence:
  - reference: PMID:25788561
    reference_title: "Hearing loss caused by a P2RX2 mutation identified in a MELAS family with a coexisting mitochondrial 3243AG mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One hundred ninety-four (194) Japanese subjects from unrelated families were enrolled in the study."
    explanation: >-
      The denominator of the series in which one P2RX2 family was found, which is the only
      quantitative handle on how uncommon this gene is among hearing loss families.
genetic:
- name: P2RX2
  notes: >-
    P2RX2 on 12q24.33 encodes the P2X2 subunit of an ATP-gated cation channel permeable to
    sodium, potassium and particularly calcium. Channels assemble as trimers, which is what
    makes a heterozygous defective subunit dominant. The receptor is expressed on sensory
    and supporting cells of the cochlea and broadly on the epithelium lining the
    endolymphatic compartment.

    Reported disease alleles are p.Val60Leu, p.Asp201Tyr, p.Gly353Arg and the stop-loss
    p.Ter350Glu. Only p.Val60Leu has been characterised functionally and only it has an
    allele-matched mouse; conclusions in this entry that rest on functional data rest on
    that one allele.

    The gene-disease relationship is classified Moderate by ClinGen's Hearing Loss Gene
    Curation Expert Panel, reaffirmed in 2022, on three missense variants in four probands.
    That is a real limit on how confidently this entry should be read, and it is not
    contradicted by anything here: the mechanism is well worked out in model systems, but
    the human genetic evidence is thin in the specific sense ClinGen measures.
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: P2RX2
    term:
      id: hgnc:15459
      label: P2RX2
  evidence:
  - reference: PMID:23345450
    reference_title: "Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we used genetics and functional studies to show that a shared cause of these disorders may be loss of function of the ATP-gated P2X(2) receptor (ligand-gated ion channel, purinergic receptor 2) that is expressed in sensory and supporting cells of the cochlea."
    explanation: The gene-disease relationship and the cell types in which the receptor acts.
  - reference: PMID:24211385
    reference_title: "A novel P2RX2 mutation in an Italian family affected by autosomal dominant nonsyndromic hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The identification of a second most likely causative mutation in P2RX2 gene further supports the possible role of this gene in causing autosomal dominant HHL."
    explanation: >-
      The first independent replication, and its hedged wording is preserved because at
      that point the gene rested on two families.
  - reference: PMID:25788561
    reference_title: "Hearing loss caused by a P2RX2 mutation identified in a MELAS family with a coexisting mitochondrial 3243AG mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two patients carried the mutation and had severe sensorineural hearing loss, while other members with MELAS (who did not carry the P2RX2 mutation) had normal hearing."
    explanation: >-
      Reads as a clean natural experiment within a family segregating the MELAS 3243A>G
      variant, with hearing loss tracking the P2RX2 allele rather than the mitochondrial
      one. Graded PARTIAL rather than SUPPORT because ClinGen's Hearing Loss expert panel
      reviewed this family and did not accept it, on the grounds that the evidence for
      pathogenicity was not strong and the variant is present in gnomAD. Curated with that
      disagreement visible rather than silently dropped or silently believed.
  - reference: CGGV:assertion_c1dae6b6-4ed7-4c5a-ba4e-bcfaba026be8-2022-09-21T160000.000Z
    reference_title: "P2RX2 / nonsyndromic genetic hearing loss (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "An additional family was reported in which hearing loss co occurred with a mitochondrial disorder, however there wasn't strong evidence in support of pathogenicity of the P2RX2 variant for this phenotype and the variant was present in gnomAD (25788561)."
    explanation: >-
      The expert panel's reason for discounting the MELAS family, quoted so a curator does
      not have to take the preceding downgrade on trust.
  - reference: CGGV:assertion_c1dae6b6-4ed7-4c5a-ba4e-bcfaba026be8-2022-09-21T160000.000Z
    reference_title: "P2RX2 / nonsyndromic genetic hearing loss (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "P2RX2 | HGNC:15459 | nonsyndromic genetic hearing loss | MONDO:0019497 | AD | Moderate | SOP9 | Hearing Loss Gene Curation Expert Panel | 2022-09-21T16:00:00.000Z"
    explanation: >-
      Graded PARTIAL because it qualifies the gene-disease relationship rather than
      supporting it outright: ClinGen classifies P2RX2 for dominant nonsyndromic hearing
      loss as Moderate, not Definitive or Strong.
  - reference: CGGV:assertion_c1dae6b6-4ed7-4c5a-ba4e-bcfaba026be8-2022-09-21T160000.000Z
    reference_title: "P2RX2 / nonsyndromic genetic hearing loss (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Functional evidence suggests a dominant negative mechanism (23345450)."
    explanation: >-
      The expert panel's reading of the coexpression result, which is why this entry
      records the variant consequence as DOMINANT_NEGATIVE rather than as a plain loss of
      function.
  - reference: PMID:41015553
    reference_title: "Construction and phenotypic analysis of p2rx2 knockout zebrafish lines."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Loss-of-function mutations in P2RX2 are known to cause autosomal dominant nonsyndromic deafness 41 (DFNA41), which manifests as high-frequency hearing loss, accelerated presbycusis, and increased susceptibility to noise-induced damage."
    explanation: >-
      A recent independent summary of the disease phenotype, cited here for the
      gene-disease framing rather than for the zebrafish result.
diagnosis:
- name: Take a noise history, and do not let it explain the audiogram away
  description: >-
    The diagnostic trap in DFNA41 is that its phenotype resembles the two commonest
    acquired causes of adult sensorineural hearing loss. Onset at 25 to 35 years with
    progressive high-frequency loss in someone with an occupational or recreational noise
    history looks like noise-induced hearing loss, and later it looks like early
    presbycusis. A dominant family history is the signal that should prompt sequencing.

    The noise history still matters, but as a modifier rather than as an alternative
    explanation: in a carrier, noise exposure and the genetic defect are the same story,
    because the gene encodes the protection against the noise. Diagnosis is by gene panel
    or exome sequencing; P2RX2 has been found through targeted enrichment panels of known
    nonsyndromic hearing loss genes.
  evidence:
  - reference: PMID:31593348
    reference_title: "Progressive Dominant Hearing Loss (Autosomal Dominant Deafness-41) and P2RX2 Gene Mutations: A Phenotype-Genotype Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our study and the review of the literature suggest that P2RX2 plays a crucial role in predisposition to noise-induced and age-related hearing loss."
    explanation: >-
      The overlap with the two acquired causes that DFNA41 is most likely to be
      misattributed to.
  - reference: PMID:25788561
    reference_title: "Hearing loss caused by a P2RX2 mutation identified in a MELAS family with a coexisting mitochondrial 3243AG mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Targeted genomic enrichment and massively parallel sequencing of all known nonsyndromic hearing loss genes were performed to identify the genetic causes of hearing loss."
    explanation: >-
      The diagnostic route by which a P2RX2 family was found, and a reminder that a
      coexisting explanation for deafness in the family did not preclude a second one.
treatments:
- name: Hearing Conservation and Noise Avoidance
  description: >-
    The one intervention that follows directly from the mechanism. A DFNA41 carrier has
    lost the purinergic adaptation that limits cochlear amplifier gain under loud sound,
    so the ordinary advice about hearing protection carries more weight for them than for
    the general population. Noise exposure has been shown to exacerbate high-frequency
    hearing loss in carriers, and in the allele-matched mouse the noise hypersensitivity is
    a distinct, separately rescuable phenotype.

    This is behavioural rather than pharmacological, and no trial has tested whether noise
    avoidance changes the trajectory in carriers - the recommendation is inferred from the
    exposure-outcome association and from the mechanism, not from an intervention study.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: noise exposure avoidance and hearing protection
  evidence:
  - reference: PMID:23345450
    reference_title: "Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Similarly, among family members heterozygous for P2RX2 p.V60L, noise exposure exacerbated high-frequency hearing loss in young adulthood."
    explanation: >-
      Graded PARTIAL because it establishes the exposure-outcome association that motivates
      avoidance, not that avoidance improves outcomes; no interventional evidence exists.
  - reference: PMID:23345450
    reference_title: "Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our results suggest that P2X(2) function is required for life-long normal hearing and for protection from exposure to noise."
    explanation: The protective role whose loss is the rationale for conservation advice.
  notes: >-
    treatment_term carries no NCIT binding. NCIT has no clinical-action term for hearing
    conservation or noise avoidance that is reachable from NCIT:C25218, so per the ontology
    contract a free-text preferred_term is correct here rather than a forced broader
    binding.
- name: Genetic Counselling with Audiologic Surveillance
  description: >-
    Counselling for a fully penetrant dominant condition with a 50 percent transmission
    risk, and serial audiometry in at-risk relatives. Onset between 25 and 35 years means a
    normal audiogram in a young adult relative is not reassurance, and it also means there
    is a long presymptomatic window in which noise conservation could in principle matter
    most.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:23345450
    reference_title: "Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "which cosegregated with fully penetrant hearing loss in the index family"
    explanation: Full penetrance, which is what makes the transmission risk counselling definite.
  - reference: PMID:31593348
    reference_title: "Progressive Dominant Hearing Loss (Autosomal Dominant Deafness-41) and P2RX2 Gene Mutations: A Phenotype-Genotype Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The onset of hearing loss was between age 25 and 35 years."
    explanation: >-
      The onset window that determines when surveillance of an at-risk relative becomes
      informative.
  notes: >-
    Hearing amplification is standard management for progressive adult sensorineural
    hearing loss, but no DFNA41-specific report documents aiding a molecularly confirmed
    patient, so it is not curated here. Genome editing is likewise not curated as a
    treatment: the published work is preclinical and is recorded under animal_models with
    its limitations stated.
- name: Cochlear Implantation
  description: >-
    Implantation for an ear that has reached profound loss. The reported DFNA41 experience
    is a single proband from a five-generation Chinese kindred carrying p.Val60Leu, with a
    satisfactory outcome. That family is also the one with earlier onset and worse hearing
    than the original DFNA41 families, so it is the part of the phenotypic range where
    implantation becomes relevant.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: cochlear implantation
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:39258340
    reference_title: "Novel Clinical Manifestation and Favorable Treatment Outcome of Cochlear Implant in a Chinese Family With Likely Pathogenic Variant of the P2RX2 Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The cochlear implant (CI) was also provided for the proband of profound deafness, resulting in satisfactory clinical outcomes."
    explanation: The implantation and its outcome in a molecularly confirmed DFNA41 proband.
  notes: >-
    treatment_term is bound to NCIT:C15329 Surgical Procedure. NCIT has no term for
    primary cochlear implantation: NCIT:C157820 Cochlear Implant is a device term and is
    not reachable from NCIT:C25218 Clinical Intervention or Procedure, and the one
    procedure term that is reachable, NCIT:C219863 Cochlear Implant Revision Surgery, names
    revision rather than first implantation. The accurate broader action term is used
    rather than a forced narrower binding. therapeutic_modality is DEVICE
    rather than SURGERY because the therapeutic platform is the implant, with surgery as
    the route of delivery.

    The outcome is reported as satisfactory without quantified speech scores in the cached
    abstract, so this entry says no more than that.
experimental_models:
- name: Patient-derived P2RX2 p.Val60Leu hiPSC lines and their CRISPR homozygous isogenic control
  experimental_model_type: IPSC_DERIVED_MODEL
  publication: PMID:30819013
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: >-
    Non-integrative hiPSCs reprogrammed from urine-derived epithelial cells of three
    members of a large Chinese kindred heterozygous for P2RX2 c.178G>T (p.Val60Leu).
  description: >-
    The only human-genetic-background model of DFNA41. Patient hiPSCs carry the causal
    allele in the patients' own genome, and CRISPR/Cas9 with single-stranded donor
    oligonucleotides converted them to a homozygous isogenic line, so allele dosage can be
    varied against a fixed background.

    What this paper reports is the construction of the lines, not a phenotype measured in
    them. There is no differentiation to otic or hair-cell fate, no electrophysiology, and
    no functional comparison between the heterozygous and homozygous lines - so the entry
    records the model as a resource that manipulates the channel defect, not as one that
    reproduces any consequence of it.
  modeled_mechanisms:
  - target: P2X2 Receptor Loss of Function
    relationship: PERTURBS
    fidelity: UNKNOWN
    description: >-
      Establishes the p.Val60Leu allele at two dosages in a human genetic background: the
      patients' own heterozygous state, and an engineered homozygote as a control for gene
      function.
    limitations: >-
      Fidelity is UNKNOWN rather than graded because nothing about the channel or its
      downstream consequences was measured in these cells. Undifferentiated iPSCs are not
      hair cells and do not express the cochlear context in which P2X2 matters, and the
      homozygous line is an engineered dosage control with no human counterpart - DFNA41
      is dominant and no homozygous patient has been reported.
    evidence:
    - reference: PMID:30819013
      reference_title: "Efficient introduction of an isogenic homozygous mutation to induced pluripotent stem cells from a hereditary hearing loss family using CRISPR/Cas9 and single-stranded donor oligonucleotides."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "we used CRISPR/Cas9 and single-stranded donor oligonucleotides to genetically establish homozygous P2RX2 c.178G>T hiPSCs (designated P2RX2-/-) from heterozygous patient-specific hiPSCs as a control to further study the pathological gene function."
      explanation: The editing step that makes this a dosage series for the node rather than a single patient line.
  evidence:
  - reference: PMID:30819013
    reference_title: "Efficient introduction of an isogenic homozygous mutation to induced pluripotent stem cells from a hereditary hearing loss family using CRISPR/Cas9 and single-stranded donor oligonucleotides."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We generated non-integrative hiPSCs from urine samples derived from three members of a large Chinese family carrying heterozygous P2RX2 c.178G>T mutations (designated P2RX2+/-) as a model to study P2RX2-mediated hereditary HL."
    explanation: The derivation of the patient lines and the allele they carry.
  - reference: PMID:30819013
    reference_title: "Efficient introduction of an isogenic homozygous mutation to induced pluripotent stem cells from a hereditary hearing loss family using CRISPR/Cas9 and single-stranded donor oligonucleotides."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Heterozygous and homozygous P2RX2-mutated hiPSC lines are good models to investigate the pathological mechanisms of P2RX2 mutations in HL pathogenesis."
    explanation: >-
      Graded PARTIAL because it is a claim about future utility, not a result: the authors
      say the lines are good models to investigate mechanisms, having investigated none.
  notes: >-
    Curated as an experimental_models entry rather than an animal_models one because
    hiPSCs are a non-animal system, and with no readouts because the publication reports
    none. It is included despite that: it is the only DFNA41 model in a human genetic
    background, and its absence would leave the entry looking as though the disease has
    only mouse and zebrafish models.
animal_models:
- name: P2rx2 V60L knock-in mouse
  species: Mouse
  genotype: P2rx2 V60L knock-in, heterozygous
  publication: PMID:33791800
  description: >-
    An allele-matched model of the human founding variant, and the one that makes DFNA41
    unusually well served among dominant deafness loci - the mouse carries the same
    substitution as the patients rather than a null. Heterozygotes begin to lose hearing at
    21 days and are deaf by six months, with progressive abnormality of inner hair cell and
    ribbon synapse morphology, and vestibular dysfunction.
  genes:
  - preferred_term: P2RX2
    term:
      id: hgnc:15459
      label: P2RX2
  modeled_mechanisms:
  - target: Inner Hair Cell and Ribbon Synapse Disorganisation
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      The only system in which inner hair cell and ribbon synapse morphology has been
      examined for this disease - no human DFNA41 temporal bone study exists, and the
      zebrafish and null-mouse work reports neither. It is allele-matched and heterozygous,
      so it reproduces the human genetic state rather than approximating it with a null.
    limitations: >-
      The time course is compressed to an extent that changes its meaning: mice are deaf by
      six months, while patients begin to lose hearing at 25 to 35 years and decline over
      decades. A phenotype that in mice looks like early-onset progressive deafness is in
      humans an adult-onset one. Synapse morphology has also not been examined in any
      human DFNA41 temporal bone, so the correspondence is assumed rather than checked.
      The vestibular dysfunction seen in these mice has no curated human counterpart: no
      vestibular testing is reported for any molecularly confirmed DFNA41 carrier, so it
      stays a model finding here rather than becoming a disease phenotype.
    readouts:
    - name: Inner hair cell and ribbon synapse morphology
      target: Inner Hair Cell and Ribbon Synapse Disorganisation
      direction: ALTERED
      interpretation: >-
        Progressive morphological abnormality rather than an all-or-none defect, appearing
        over the same period as the hearing decline.
      evidence:
      - reference: PMID:33791800
        reference_title: "Generation and characterization of a P2rx2 V60L mouse model for DFNA41."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Abnormal morphology of the inner hair cells and ribbon synapses was progressively observed in KI animals suggesting that P2rx2 plays a role in the membrane spatial location of the ribbon synapses."
        explanation: The structural measurement behind this readout.
    - name: Auditory function over time
      target: Inner Hair Cell and Ribbon Synapse Disorganisation
      direction: DECREASED
      interpretation: >-
        Progressive hearing loss from 21 days to deafness by six months. The readout is
        named for function rather than for threshold because the cited sentence reports
        hearing loss, and a threshold moves in the opposite direction to the function it
        measures.
      evidence:
      - reference: PMID:33791800
        reference_title: "Generation and characterization of a P2rx2 V60L mouse model for DFNA41."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Heterozygous KI mice started to exhibit hearing loss at 21-day-old and progressed to deafness by 6-month-old."
        explanation: The functional time course in the allele-matched heterozygote.
    evidence:
    - reference: PMID:33791800
      reference_title: "Generation and characterization of a P2rx2 V60L mouse model for DFNA41."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We generated and characterized a knock-in mouse model based on human p.V60L mutation that recapitulates the human phenotype."
      explanation: The authors' claim of recapitulation, on the same allele as the patients.
- name: P2rx2 null mouse
  species: Mouse
  genotype: P2rx2 null, homozygous
  publication: PMID:23592720
  description: >-
    The model in which the purinergic adaptation mechanism was established. Nulls lack
    ATP-gated conductance across the cochlear partition including ATP-gated inward current
    in hair cells, fail to develop the temporary threshold shift that wild-type mice
    develop under sustained 85 dB noise, and are more vulnerable than wild-type mice to
    permanent loss at 95 dB and above.
  genes:
  - preferred_term: P2RX2
    term:
      id: hgnc:15459
      label: P2RX2
  modeled_mechanisms:
  - target: Loss of Purinergic Adaptation to Elevated Sound Levels
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Defines the mechanism, with the conductance measurement, the behavioural threshold
      measurement and the supporting emission and gain data all in one system. Nothing
      equivalent can be measured in patients.
    limitations: >-
      A homozygous null against a human heterozygous state, so it models complete loss of
      the mechanism rather than the partial loss a carrier has - and partial is the
      clinically relevant condition, since the dominant allele degrades but does not
      abolish the function of channels containing wild-type subunits. Sound levels and
      exposure schedules are also experimental rather than matched to any human exposure
      history.
    readouts:
    - name: Noise-induced temporary threshold shift
      target: Loss of Purinergic Adaptation to Elevated Sound Levels
      direction: ABOLISHED
      interpretation: >-
        The adaptive response to moderate sustained noise does not occur in the absence of
        P2X2. This is the defining measurement of the node.
      evidence:
      - reference: PMID:23592720
        reference_title: "ATP-gated ion channels mediate adaptation to elevated sound levels."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "In mice null for the P2RX2 gene (encoding the P2X2 receptor subunit), sustained 85-dB noise failed to elicit the TTS that wild-type (WT) mice developed."
        explanation: The threshold-shift measurement in the null.
    - name: ATP-gated conductance across the cochlear partition
      target: Loss of Purinergic Adaptation to Elevated Sound Levels
      direction: ABOLISHED
      interpretation: >-
        The electrophysiological substrate of the adaptation is absent, which is what makes
        the behavioural result mechanistic rather than merely correlated.
      evidence:
      - reference: PMID:23592720
        reference_title: "ATP-gated ion channels mediate adaptation to elevated sound levels."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "P2RX2-null mice lacked ATP-gated conductance across the cochlear partition, including loss of ATP-gated inward current in hair cells."
        explanation: The direct conductance measurement in the null.
    evidence:
    - reference: PMID:23592720
      reference_title: "ATP-gated ion channels mediate adaptation to elevated sound levels."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These data indicate that a significant component of TTS represents P2X2 receptor-dependent purinergic hearing adaptation that underpins the upper physiological range of hearing."
      explanation: The conclusion this node curates, drawn from this model.
  - target: Noise-Exacerbated High-Frequency Hearing Impairment
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The gene-environment interaction reproduced under controlled exposure, which is the
      thing human observation cannot deliver because noise history in a family is recalled
      rather than measured.
    limitations: >-
      Homozygous null rather than the human heterozygous state, and the exposure is a
      defined laboratory protocol rather than a lifetime of variable occupational and
      recreational sound. The direction and the interaction are reproduced; the dose is not
      comparable.
    readouts:
    - name: High-frequency hearing after early continuous moderate noise
      target: Noise-Exacerbated High-Frequency Hearing Impairment
      direction: DECREASED
      interpretation: >-
        Controlled early exposure produces the same high-frequency loss reported in exposed
        human carriers.
      evidence:
      - reference: PMID:23345450
        reference_title: "Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "P2RX2-null mice developed severe progressive hearing loss, and their early exposure to continuous moderate noise led to high-frequency hearing loss as young adults."
        explanation: The controlled-exposure measurement.
    evidence:
    - reference: PMID:23592720
      reference_title: "ATP-gated ion channels mediate adaptation to elevated sound levels."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "At higher sound levels (≥95 dB), additional processes dominated TTS, and P2RX2-null mice were more vulnerable than WT mice to permanent hearing loss due to hair cell synapse disruption."
      explanation: >-
        Vulnerability to permanent noise damage measured in the same null line, which is
        what makes it informative for the noise-exacerbated phenotype rather than only for
        the adaptation node.
- name: P2rx2 V61L knock-in mouse treated with AAV-delivered SaCas9
  species: Mouse
  genotype: P2rx2 V61L/+ knock-in treated with AAV2 SaCas9-sgRNA targeting the mutant allele
  publication: PMID:41090360
  description: >-
    Allele-specific genome editing in the mature inner ear of the knock-in heterozygote.
    Local injection produced efficient and specific editing that abolished the mutation
    without notable off-target effects or AAV genome integration, restored long-term
    auditory and vestibular function, and protected the animals from noise
    hypersensitivity. Intervention at a juvenile stage broadened the frequency range
    rescued. A gRNA effective against the human V60L allele was also identified.
  genes:
  - preferred_term: P2RX2
    term:
      id: hgnc:15459
      label: P2RX2
  modeled_mechanisms:
  - target: Loss of Purinergic Adaptation to Elevated Sound Levels
    relationship: RESCUES
    fidelity: MODERATE
    description: >-
      The forward test of the mechanism. Removing the mutant allele restores not just
      hearing but specifically the resistance to noise, which is the functional signature
      of the purinergic adaptation this entry places at the centre of the disease. That the
      noise phenotype rescues separately is the strongest available evidence that it is
      mechanistically distinct from the baseline progressive loss rather than a
      consequence of it.
    limitations: >-
      Editing removes the dominant allele in a mouse whose own P2rx2 numbering differs
      (V61L against human V60L) and whose disease runs its course in months rather than
      decades, so the treated window has no clear human equivalent. The authors show that
      juvenile intervention broadens the rescued frequency range, which implies that later
      treatment does less - and human DFNA41 is not diagnosable until adulthood, well past
      any comparable stage. The human gRNA was identified, not tested in patients.
    readouts:
    - name: Resistance to noise-induced hearing loss after editing
      target: Loss of Purinergic Adaptation to Elevated Sound Levels
      direction: RESTORED
      interpretation: >-
        Protection against noise is restored, not merely baseline hearing, which maps the
        rescue onto the adaptation mechanism specifically. Named for resistance rather
        than susceptibility so that RESTORED reads in the same direction as the measure.
      evidence:
      - reference: PMID:41090360
        reference_title: "Single-dose genome editing therapy rescues auditory and vestibular functions in adult mice with DFNA41 deafness."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Editing further protects P2rx2V61L/+ mice from hypersensitivity to noise-induced hearing loss, a phenotype also observed in patients with DFNA41."
        explanation: >-
          The noise-specific rescue, and the authors' own statement that the phenotype
          rescued is one patients have.
    - name: Auditory and vestibular function after editing
      target: Loss of Purinergic Adaptation to Elevated Sound Levels
      direction: RESTORED
      interpretation: Long-term restoration of both systems from a single dose.
      evidence:
      - reference: PMID:41090360
        reference_title: "Single-dose genome editing therapy rescues auditory and vestibular functions in adult mice with DFNA41 deafness."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Editing effectively restores long-term auditory and vestibular function."
        explanation: The primary functional outcome of the intervention.
    evidence:
    - reference: PMID:41090360
      reference_title: "Single-dose genome editing therapy rescues auditory and vestibular functions in adult mice with DFNA41 deafness."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We demonstrate that local injection in adult mice results in efficient and specific editing that abolishes the mutation without notable off-target effects or AAV genome integration."
      explanation: >-
        Establishes that the intervention did what it was supposed to at the molecular
        level, which is what licenses reading the functional rescue as mechanism-specific.
  evidence:
  - reference: PMID:41090360
    reference_title: "Single-dose genome editing therapy rescues auditory and vestibular functions in adult mice with DFNA41 deafness."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Intervention in mice at a juvenile stage broadens the frequency range rescued, highlighting the importance of early intervention."
    explanation: >-
      Graded PARTIAL because it qualifies the rescue rather than supporting it: the benefit
      is timing-dependent, and the timing that works best has no counterpart in a disease
      diagnosed in adults.
- name: p2rx2 knockout zebrafish
  species: Zebrafish
  genotype: p2rx2 knockout (66 bp insertion introducing a premature TAA), homozygous
  publication: PMID:41015553
  description: >-
    A CRISPR/Cas9 loss-of-function line in the P2RX2 orthologue, and the only non-mammalian
    model of this gene's auditory role. Homozygous mutants develop normally but lose hair
    cell density in the otolith region - the zebrafish saccule, which is the auditory
    organ - while lateral line neuromasts are spared, and their auditory evoked potential
    thresholds are raised at every frequency tested.
  genes:
  - preferred_term: P2RX2
    term:
      id: hgnc:15459
      label: P2RX2
  modeled_mechanisms:
  - target: Progressive Sensorineural Hearing Impairment
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Reproduces sensorineural hearing loss from p2rx2 loss of function, with a hair cell
      correlate, in a lineage separated from mammals by several hundred million years. Its
      value here is convergence rather than detail: the auditory requirement for this
      channel is not a property of the mouse cochlea.
    limitations: >-
      A homozygous null in an orthologue, against a human heterozygous missense state in
      which the dominant mechanism is subunit poisoning - so it tests whether the gene is
      needed for hearing, not how the human allele causes disease. Zebrafish have no
      cochlea; hearing is transduced by the saccule, and the frequency range measured (600
      to 2 000 Hz) has no correspondence to the high-frequency human loss. Thresholds were
      measured at one age in nine fish per group, so the progression that names this
      phenotype is not shown.
    readouts:
    - name: Auditory evoked potential threshold
      target: Progressive Sensorineural Hearing Impairment
      direction: INCREASED
      interpretation: >-
        Thresholds rose at all four frequencies tested, which is what reduced hearing
        sensitivity looks like when the measure is a threshold rather than a function.
      evidence:
      - reference: PMID:41015553
        reference_title: "Construction and phenotypic analysis of p2rx2 knockout zebrafish lines."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "The AEP thresholds of the homozygous mutant zebrafish with the p2rx2 gene were significantly higher compared to those of the wild type zebrafish at stimulation frequencies of 600, 800, 1 000, and 2 000 Hz"
        explanation: The functional measurement behind this readout, at four frequencies.
    - name: Hair cell density in the otolith region
      target: Progressive Sensorineural Hearing Impairment
      direction: DECREASED
      interpretation: >-
        The structural correlate, and it is anatomically selective: the auditory otolith
        organ loses hair cells while the lateral line, whose hair cells are molecularly
        similar, does not.
      evidence:
      - reference: PMID:41015553
        reference_title: "Construction and phenotypic analysis of p2rx2 knockout zebrafish lines."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "a marked reduction in hair cell density was evident in the otolith region of p2rx2 gene knockout zebrafish compared to controls"
        explanation: The hair cell count behind this readout.
      - reference: PMID:41015553
        reference_title: "Construction and phenotypic analysis of p2rx2 knockout zebrafish lines."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "no significant differences were observed in the number or arrangement of hair cells within the lateral line region between p2rx2 gene knockout zebrafish and the control group"
        explanation: >-
          Graded PARTIAL because it bounds the readout rather than supporting it: the loss
          is confined to the auditory organ, so the measure is not a general hair cell
          defect.
    evidence:
    - reference: PMID:41015553
      reference_title: "Construction and phenotypic analysis of p2rx2 knockout zebrafish lines."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "p2rx2 deficiency caused hair cell defects in the otolith region and increased auditory thresholds across frequencies, indicating its key role in maintaining zebrafish auditory hair cell function and hearing perception"
      explanation: >-
        The authors' own summary of what the line shows, which is what makes it informative
        for the hearing loss rather than only for the gene.
references:
- reference: PMID:20301607
  title: Genetic Hearing Loss Overview.
  tags:
  - GeneReviews
discussions:
- discussion_id: dfna41_carrier_noise_dose_response
  kind: KNOWLEDGE_GAP
  prompt: >-
    How much noise is too much for a P2RX2 carrier? Is there a dose below which a carrier
    is no worse off than a non-carrier, and does hearing conservation started before onset
    change the trajectory?
  attaches_to:
  - environmental#Occupational and recreational noise exposure
  - treatments#Hearing Conservation and Noise Avoidance
  - phenotypes#Noise-Exacerbated High-Frequency Hearing Impairment
  rationale: >-
    This entry curates noise avoidance as a treatment on the strength of an association and
    a mechanism, and that is the weakest treatment claim in the file. The evidence is that
    exposed carriers did worse than unexposed ones in one family, and that null mice
    exposed to a laboratory protocol lost high frequencies. Neither tells a 22-year-old
    carrier whether to change career, and neither establishes that protection helps.

    The gap is quantitative and it is answerable. Occupational noise exposure limits are
    built on population dose-response data in people with intact purinergic adaptation; a
    carrier has, by hypothesis, a left-shifted curve, but nobody has measured where. The
    mouse work gives a hint that the shift is real at moderate levels, since the difference
    between null and wild-type appears at 85 dB - below the level at which additional
    damage processes take over - which is squarely inside the range of ordinary
    occupational exposure rather than at the extremes.

    What would settle it is a carrier cohort with dosimetry rather than recalled exposure,
    audiometry over years, and non-carrier relatives as controls. The founding kindred is
    six generations deep and has already been followed for ten years, so the ascertainment
    problem is mostly solved. Until then the counselling advice in this entry should be
    read as mechanistically motivated rather than evidence-based, which is how the
    treatment entry states it.
  evidence:
  - reference: PMID:23345450
    reference_title: "Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Similarly, among family members heterozygous for P2RX2 p.V60L, noise exposure exacerbated high-frequency hearing loss in young adulthood."
    explanation: >-
      Graded PARTIAL: an exposure-outcome association without exposure quantification,
      which is exactly the limitation the gap is about.
  - reference: PMID:23592720
    reference_title: "ATP-gated ion channels mediate adaptation to elevated sound levels."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In mice null for the P2RX2 gene (encoding the P2X2 receptor subunit), sustained 85-dB noise failed to elicit the TTS that wild-type (WT) mice developed."
    explanation: >-
      Locates the divergence at a specific, ordinary sound level, which is what makes the
      dose question concrete rather than abstract.
  - reference: PMID:23592720
    reference_title: "ATP-gated ion channels mediate adaptation to elevated sound levels."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "At higher sound levels (≥95 dB), additional processes dominated TTS, and P2RX2-null mice were more vulnerable than WT mice to permanent hearing loss due to hair cell synapse disruption."
    explanation: >-
      Shows that the relationship between genotype and sound level is not monotonic in
      kind: different processes dominate at different intensities, so a single exposure
      limit may not be the right answer.
  - reference: PMID:31593348
    reference_title: "Progressive Dominant Hearing Loss (Autosomal Dominant Deafness-41) and P2RX2 Gene Mutations: A Phenotype-Genotype Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Progressive hearing impairment was confirmed by history and by audiological follow-up testing in all the patients."
    explanation: >-
      Evidence that longitudinal follow-up of this kindred is already established, which is
      what makes the proposed dosimetry study feasible rather than hypothetical.
  proposed_experiments:
  - experiment_id: exp_dfna41_carrier_noise_dosimetry_cohort
    name: Longitudinal noise dosimetry in P2RX2 carriers and non-carrier relatives
    description: >-
      Enrol carriers and genotype-negative relatives from known DFNA41 kindreds, measure
      cumulative noise exposure by personal dosimetry rather than by questionnaire, and
      follow pure tone and extended high-frequency audiometry annually. Model threshold
      change against cumulative dose separately by genotype to estimate whether the
      exposure-response curve is shifted and by how much.
    would_support:
    - phenotypes#Noise-Exacerbated High-Frequency Hearing Impairment
    supporting_outcome:
    - >-
      Carriers show a steeper threshold-versus-dose slope than non-carrier relatives, with
      separation beginning at exposures within current occupational limits, which would
      justify genotype-specific exposure advice and give a number to give patients.
    would_refute:
    - phenotypes#Noise-Exacerbated High-Frequency Hearing Impairment
    refuting_outcome:
    - >-
      Carrier and non-carrier slopes are indistinguishable and the carrier decline is
      independent of measured dose, which would mean the reported exacerbation reflects
      recall bias or confounding and that noise avoidance should be dropped from this
      entry as a mechanism-specific recommendation.
- discussion_id: dfna41_null_versus_heterozygous_mechanism
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    The purinergic adaptation mechanism was established in homozygous P2rx2 null mice,
    but DFNA41 patients are heterozygous for a subunit that poisons trimeric channels
    partially. Is adaptation abolished in carriers, or merely reduced, and does that
    difference change what noise does to them?
  attaches_to:
  - pathophysiology#Loss of Purinergic Adaptation to Elevated Sound Levels
  - animal_models#P2rx2 null mouse
  rationale: >-
    The two halves of this entry's mechanism come from different genotypes. The adaptation
    node rests on null mice, where the conductance is absent outright. Patients carry one
    mutant allele in a channel built from three subunits, and the measured consequence of
    that is a significant reduction in ATP-activated permeability on coexpression - a
    reduction, not an abolition. So the human condition is a partial loss of a graded
    protective mechanism, and the model that defined the mechanism is a complete loss of it.

    This matters for more than tidiness. If adaptation in carriers is reduced but present,
    there may be a sound level below which it still engages, which is precisely the dose
    question a carrier needs answered. If it is effectively abolished at ordinary sound
    levels despite the residual wild-type channels, the carrier is in the same position as
    the null mouse and the advice is simpler and stricter. Nobody has measured
    noise-induced temporary threshold shift in a P2rx2 V60L heterozygous mouse, which is
    the obvious experiment and uses a model that already exists.

    The gene-editing study bears on this indirectly and encouragingly: rescuing the
    heterozygote restored noise resistance, which implies the heterozygous state does have
    a noise phenotype to rescue. But that is an endpoint measurement, not a measurement of
    the adaptation itself.
  evidence:
  - reference: PMID:23345450
    reference_title: "Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Coexpression of mutant and WT P2X(2) receptor subunits significantly reduced ATP-activated membrane permeability."
    explanation: >-
      The human genetic state is partial loss, quantified. That is the mismatch with the
      null model.
  - reference: PMID:23592720
    reference_title: "ATP-gated ion channels mediate adaptation to elevated sound levels."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "P2RX2-null mice lacked ATP-gated conductance across the cochlear partition, including loss of ATP-gated inward current in hair cells."
    explanation: >-
      The model state is complete loss, also measured. Setting the two quotes side by side
      is the substance of the mismatch.
  - reference: PMID:41090360
    reference_title: "Single-dose genome editing therapy rescues auditory and vestibular functions in adult mice with DFNA41 deafness."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Editing further protects P2rx2V61L/+ mice from hypersensitivity to noise-induced hearing loss, a phenotype also observed in patients with DFNA41."
    explanation: >-
      Graded PARTIAL: indirect evidence that the heterozygote does have a noise phenotype,
      since it can be rescued, but it does not measure purinergic adaptation in that
      genotype.
  proposed_experiments:
  - experiment_id: exp_dfna41_tts_in_heterozygous_knockin
    name: Temporary threshold shift measurement in P2rx2 V60L heterozygous mice
    description: >-
      Run the same graded sound-level protocol used in the null study - sustained exposure
      at 85 dB and at 95 dB with auditory brainstem response and distortion product
      otoacoustic emission recordings before, during and after - in P2rx2 V60L heterozygous
      knock-in mice, wild-type littermates, and P2rx2 nulls in the same experiment, at an
      age before the knock-in has lost baseline hearing.
    would_support:
    - pathophysiology#Loss of Purinergic Adaptation to Elevated Sound Levels
    supporting_outcome:
    - >-
      Heterozygotes show a reduced but measurable temporary threshold shift, intermediate
      between wild-type and null, which would establish adaptation as graded with gene
      dosage and would give a sound level at which carrier protection still engages.
    would_refute:
    - pathophysiology#Loss of Purinergic Adaptation to Elevated Sound Levels
    refuting_outcome:
    - >-
      Heterozygotes are indistinguishable from wild-type in threshold shift while still
      developing progressive hearing loss, which would mean the adaptation defect is not
      the mechanism of DFNA41 in carriers and would push the entry's centre of gravity
      toward the synaptic node instead.
- discussion_id: dfna41_gene_disease_validity
  kind: KNOWLEDGE_GAP
  prompt: >-
    P2RX2 is classified Moderate rather than Definitive for dominant nonsyndromic hearing
    loss. What would move it, and does the strength of the mechanistic evidence make the
    human genetic evidence look better than it is?
  attaches_to:
  - genetic#P2RX2
  - disease#Autosomal Dominant Nonsyndromic Hearing Loss 41
  rationale: >-
    This entry is mechanistically rich and genetically thin, and the two can be mistaken
    for one another. The purinergic adaptation story rests on a null mouse, a knock-in
    mouse, a genome-editing rescue and direct electrophysiology - as good a mechanistic
    case as most deafness genes have. The human case rests on three missense variants in
    four probands, which is why ClinGen's Hearing Loss expert panel classified the
    gene-disease relationship Moderate in 2018 and left it at Moderate on reevaluation in
    2022 even after adding a new case and a new mouse model.

    The panel's own framing is worth keeping in view: more evidence is needed to establish
    the relationship definitively, and no convincing contradictory evidence has emerged.
    That is not scepticism about the gene, it is a statement that segregation and case
    counts have not accumulated. What would move the classification is more independent
    probands with segregation, which for an adult-onset dominant condition means finding
    families rather than waiting for them.

    Practically, the caution belongs at the point of variant interpretation rather than in
    the mechanism. A novel P2RX2 missense variant in an isolated adult with progressive
    high-frequency loss and a noise history is exactly the situation in which a Moderate
    gene-disease classification should restrain a pathogenic call - and it is also the
    situation this entry's diagnosis section warns is easy to misattribute in the other
    direction. Both errors are available, and this entry deliberately does not resolve
    that tension by hiding either half.
  evidence:
  - reference: CGGV:assertion_c1dae6b6-4ed7-4c5a-ba4e-bcfaba026be8-2022-09-21T160000.000Z
    reference_title: "P2RX2 / nonsyndromic genetic hearing loss (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged."
    explanation: The panel's summary judgement, in its own words.
  - reference: CGGV:assertion_c1dae6b6-4ed7-4c5a-ba4e-bcfaba026be8-2022-09-21T160000.000Z
    reference_title: "P2RX2 / nonsyndromic genetic hearing loss (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Three missense variants that have been reported in four probands in four publications are included in this curation"
    explanation: >-
      The size of the human genetic evidence base, which is the specific thing that is
      thin - not the mechanism.
  - reference: CGGV:assertion_c1dae6b6-4ed7-4c5a-ba4e-bcfaba026be8-2022-09-21T160000.000Z
    reference_title: "P2RX2 / nonsyndromic genetic hearing loss (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Although a new case with hearing loss (29986705) and a new knock-in mouse model with progressive hearing loss (33791800) were scored, the classification did not change (SOP Version 9)."
    explanation: >-
      The 2022 reevaluation, which is informative about what does not move a
      classification: an additional case and the allele-matched knock-in this entry relies
      on were both scored and left it at Moderate.
  - reference: CGGV:assertion_c1dae6b6-4ed7-4c5a-ba4e-bcfaba026be8-2022-09-21T160000.000Z
    reference_title: "P2RX2 / nonsyndromic genetic hearing loss (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Loss of the P2RX2 receptor in mice increases susceptibility to noise-induced hearing loss, and a significant correlation was found in a large Chinese family between noise exposure during adolescence and severity of hearing loss (PMIDs: 23345450, 33791800)."
    explanation: >-
      An independent restatement of the gene-environment interaction, and a more specific
      one than the source papers give: the human correlation is with noise exposure during
      adolescence and with severity, in a large family.
📚

References & Deep Research

References

1
PMID:20301607
Genetic Hearing Loss Overview.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Autosomal Dominant Nonsyndromic Hearing Loss 41 (DFNA41): Research Report
Edison Scientific Literature 28 citations 2026-08-28T11:38:18.063067

Autosomal Dominant Nonsyndromic Hearing Loss 41 (DFNA41): Research Report

Executive summary

Autosomal dominant nonsyndromic hearing loss 41 (DFNA41) is an ultrarare, postlingual, progressive sensorineural hearing disorder caused by heterozygous pathogenic variation in P2RX2, most convincingly NM_174873:c.178G>T, p.(Val60Leu). In the defining families, hearing loss was bilateral and symmetric, began at 12–20 years, initially emphasized high frequencies, and subsequently involved all frequencies. The original pedigree showed complete reported penetrance, severe thresholds of approximately 60–70 dB by age 20, and relative stabilization by the fourth decade. Occupational noise significantly worsened high-frequency hearing, making DFNA41 an unusually well-supported example of a Mendelian gene–environment interaction. (yan2013mutationofthe pages 1-2, yan2013mutationofthe pages 2-3)

P2X2 is an extracellular ATP-gated trimeric cation channel involved in cochlear purinergic adaptation. Val60Leu reaches the plasma membrane but abolishes ATP-evoked current in homomeric receptors and markedly impairs heteromeric-channel permeability. Mouse and cellular models implicate impaired cochlear adaptation, hair-cell and ribbon-synapse pathology, neural degeneration, and reduced resilience to acoustic stress. Current treatment remains audiological and rehabilitative. A 2025 study—beyond the requested 2023–2024 priority window—reported mutation-selective AAV2–SaCas9 editing that rescued auditory, vestibular, and noise-susceptibility phenotypes in adult mice; this remains preclinical. (yan2013mutationofthe pages 4-5, chen2021generationandcharacterization pages 2-3, wei2025singledosegenomeediting pages 2-5, wei2025singledosegenomeediting pages 1-2)

The following table summarizes the principal curation-ready findings.

domain evidence-based finding ontology/identifier suggestions evidence level/limitations
Disease identity Autosomal Dominant Nonsyndromic Hearing Loss 41 (DFNA41) is a rare Mendelian hearing-loss subtype defined from aggregated disease-level and pedigree-based human genetics data; OMIM identifier reported as 608224 (yan2013mutationofthe pages 1-2, yan2013mutationofthe pages 2-3) OMIM: 608224; MONDO: not established from retrieved evidence; MeSH/ICD/Orphanet not confirmed in retrieved sources Human primary evidence for disease existence and mapping; some cross-database identifiers unavailable in retrieved context
Causal gene/variant The best-supported causal lesion is heterozygous P2RX2 c.178G>T, p.Val60Leu (p.V60L; NM_174873), identified in two unrelated Chinese families and absent from >7,000 controls (yan2013mutationofthe pages 2-3) P2RX2; HGNC gene symbol: P2RX2; variant: c.178G>T, p.Val60Leu Human primary evidence is strong for this variant; broader allelic spectrum was not directly resolved from retrieved full primary reports
Inheritance Inheritance is autosomal dominant with perfect cosegregation in the index pedigree, LOD score 13.3, and 100% penetrance among reported heterozygous carriers (yan2013mutationofthe pages 2-3) HP:0000006 Autosomal dominant inheritance Human pedigree evidence strong, but penetrance estimate is based on a small number of families
Core phenotype Affected individuals have bilateral, symmetrical, progressive sensorineural hearing loss, first detected at 12-20 years, ultimately involving all frequencies; severity reached about 60-70 dB by age 20 in the original family (yan2013mutationofthe pages 1-2, yan2013mutationofthe pages 2-3) HP:0008619 Progressive hearing impairment; HP:0000407 Sensorineural hearing impairment; HP:0011453 Bilateral hearing impairment Human primary evidence; natural-history estimates remain limited because only a few families are published
Audiometric pattern/symptoms Hearing loss is typically high-frequency early, with high-frequency tinnitus reported; occupational noise exposure worsened high-frequency thresholds in mutation carriers (n=12 exposed vs n=9 unexposed, P=0.001) (yan2013mutationofthe pages 1-2, yan2013mutationofthe pages 2-3) HP:0000366 Hearing impairment; HP:0000358 Tinnitus; HP:0001644 Dilated? not applicable; no exact HPO for noise susceptibility confirmed here Human evidence for tinnitus/noise interaction comes from small family-based comparisons
Gene-environment interaction DFNA41 shows a documented gene-environment interaction: moderate noise exposure exacerbates hearing loss in carriers, indicating increased susceptibility to noise-induced hearing loss (yan2013mutationofthe pages 1-2, yan2013mutationofthe pages 2-3, yan2013mutationofthe pages 5-6) Exposure concept: occupational noise; phenotype concept: noise-induced hearing loss susceptibility Human evidence present but based on observational family histories rather than prospective exposure studies
Molecular function P2X2 is an extracellular ATP-gated trimeric cation channel expressed in cochlear sensory and supporting tissues; the p.V60L change abolishes ATP-evoked inward current in homomeric channels and impairs permeability in heteromeric channels (yan2013mutationofthe pages 1-2, yan2013mutationofthe pages 2-3, mittal2016molecularstructureand pages 10-11) GO:0005230 extracellular ligand-gated ion channel activity; GO:0006811 ion transport Human/in vitro evidence strong for loss of channel function; detailed downstream pathway mapping remains incomplete
Pathomechanism The mutant receptor localizes to plasma membrane but is functionally defective, supporting a loss-of-function/gating defect rather than mislocalization; inferred disease chain is impaired purinergic cochlear adaptation and reduced protection from noise/age-related stress (yan2013mutationofthe pages 4-5, mittal2016molecularstructureand pages 10-11) GO:0007166 cell surface receptor signaling pathway; GO:0050890 cognition? not applicable; inferred cochlear homeostasis terms Mixed evidence: human cell assays plus model inference; some mechanistic steps remain inferred rather than directly proven in patients
Anatomy/cell types P2X2 expression/localization has been shown in organ of Corti, inner and outer hair cells, supporting cells, spiral ganglion neurons, and epithelial lining of the cochlea; mouse KI work also found expression in crista ampullaris (chen2021generationandcharacterization pages 2-3, yan2013mutationofthe pages 1-2) UBERON: cochlea, organ of Corti; CL: hair cell, supporting cell, spiral ganglion neuron Primarily model/histologic evidence; exact human single-cell localization was not retrieved
Diagnostics Recommended diagnosis is clinical audiologic assessment plus molecular confirmation by hearing-loss gene panel, WES, or targeted P2RX2 testing in the setting of dominant postlingual progressive SNHL and family history; temporal bone CT can be normal (yan2013mutationofthe pages 2-3, wei2025singledosegenomeediting pages 1-2) NCIT: Genetic Testing; audiology concepts: ABR/audiometry as applicable Human evidence supports genetic confirmation; no DFNA41-specific formal guideline was retrieved
Current treatment Current management is supportive: longitudinal audiologic follow-up, strict noise avoidance/protection, hearing aids, cochlear implantation when severity/function warrant it, and rehabilitation/genetic counseling (wei2025singledosegenomeediting pages 1-2, alde2023autosomaldominantnonsyndromic pages 16-17) NCIT: Hearing Aid Device; NCIT: Cochlear Implantation; NCIT: Genetic Counseling Largely inferred from standard care for dominant progressive SNHL; no DFNA41-specific interventional outcome series retrieved
Approved therapies/trials No approved molecular therapy specific to DFNA41 was identified, and no relevant registered interventional clinical trial was retrieved in the tool search (wei2025singledosegenomeediting pages 1-2) NCIT: Gene Therapy (experimental only) Evidence reflects search results, not proof of global absence; trial landscape can change rapidly
Mouse models P2rx2-null mice develop progressive hearing loss and greater noise vulnerability; the P2rx2 V61L knock-in mouse recapitulates DFNA41-related auditory disease, with hearing loss beginning at postnatal day 21 and progressing to deafness by 6 months, plus vestibular dysfunction and inner hair cell/ribbon synapse abnormalities (yan2013mutationofthe pages 1-2, chen2021generationandcharacterization pages 1-2, chen2021generationandcharacterization pages 1-1, chen2021generationandcharacterization pages 2-3) MGI mouse P2rx2 models; phenotype terms: hearing loss, vestibular dysfunction Strong model evidence; disease onset is earlier and progression faster than in humans
Cellular models Patient-derived non-integrative hiPSCs from urine samples and CRISPR-engineered homozygous/heterozygous P2RX2 p.V60L hiPSC lines were generated as mechanistic models for hereditary hearing loss (dong2019efficientintroductionof pages 1-3) iPSC disease model; P2RX2-mutated hiPSC In vitro model only; no therapeutic efficacy in humans demonstrated
Recent translational development A 2025 preclinical study used AAV2-delivered SaCas9/sgRNA allele-specific editing in adult P2rx2V61L/+ mice, with efficient mutant-selective editing, minimal detected off-target effects, no notable AAV integration in cochlear hair cells, and rescue of long-term auditory/vestibular function plus protection from noise hypersensitivity (wei2025singledosegenomeediting pages 1-2, wei2025singledosegenomeediting pages 2-5, wei2025singledosegenomeediting pages 5-7) NCIT: CRISPR-Cas9 Genome Editing; NCIT: Adeno-Associated Virus Vector Model-only, post-2024 preclinical evidence; not yet a human therapy or clinical trial
Evidence gaps No robust disease-specific prevalence/incidence, survival, mortality, protective genetic modifiers, epigenetic biomarkers, or validated prognostic biomarkers were found in retrieved evidence (yan2013mutationofthe pages 1-2, wei2025singledosegenomeediting pages 1-2) Knowledge-base flag: data not available Important to distinguish absence of evidence from evidence of absence

Table: This table condenses the most actionable evidence on DFNA41 across identity, genetics, phenotype, mechanism, diagnosis, treatment, and models. It distinguishes human primary findings from model-based and inferred information to support knowledge-base curation.

1. Disease information

Definition

DFNA41 is a Mendelian, autosomal dominant, nonsyndromic sensorineural hearing loss. “Nonsyndromic” means that hearing impairment is the defining human clinical manifestation rather than one component of a reproducible multisystem syndrome. The disease was initially delineated in a six-generation family from Sichuan, China, and later associated with P2RX2 in that family and a second unrelated Chinese family. (yan2013mutationofthe pages 1-2, yan2013mutationofthe pages 2-3)

Identifiers and synonyms

  • Preferred name: Autosomal dominant nonsyndromic hearing loss 41
  • Common synonyms: DFNA41; autosomal dominant deafness 41; deafness, autosomal dominant 41; P2RX2-related dominant hearing loss
  • OMIM: 608224 (DFNA41/deafness, autosomal dominant 41)
  • Causal gene: P2RX2, purinergic receptor P2X 2
  • Locus: chromosome 12q24–qter; the refined original interval was hg19 chr12:129,051,849–133,851,895. (yan2013mutationofthe pages 1-2)
  • MONDO: A disease-specific MONDO identifier could not be verified from the retrieved evidence. Use the verified OMIM identifier and parent concepts such as hereditary nonsyndromic sensorineural hearing loss until an ontology release confirms a dedicated MONDO record.
  • Orphanet: No disease-specific Orphanet identifier was verified.
  • ICD-10/ICD-11: No DFNA41-specific billing code exists in the retrieved evidence; code the manifest bilateral sensorineural hearing loss and genetic etiology as permitted locally.
  • MeSH: No uniquely specific DFNA41 heading was verified; broader concepts include Hearing Loss, Sensorineural and Hearing Loss, Hereditary.

The evidence is principally aggregated disease-level information derived from published family studies, not routine EHR-derived patient-level surveillance. The foundational evidence nevertheless consists of individual family members’ genotypes, audiograms, exposure histories, and clinical examinations. (yan2013mutationofthe pages 1-2, yan2013mutationofthe pages 2-3)

2. Etiology, risk, protection, and gene–environment interaction

Primary cause

The strongest established cause is a germline heterozygous P2RX2 missense variant, c.178G>T, p.(Val60Leu). It cosegregated perfectly with hearing loss in the index pedigree, yielding a LOD score of 13.3, and penetrance among reported heterozygotes was 100%. Screening 65 additional dominant nonsyndromic hearing-loss families identified the same variant in another unrelated Chinese family. It was absent from 7,000 controls—4,300 European-ancestry, 2,200 African-American, and 500 Chinese individuals—giving historical estimated frequencies below 0.0001 in the mixed sample and below 0.001 in the Chinese sample. (yan2013mutationofthe pages 2-3)

This variant is germline, not somatic. Published reports describe additional P2RX2 variants in hearing-loss families, including an Italian family and an Iranian stop-loss report, but the retrieved full-text evidence was insufficient to curate their exact HGVS notation, segregation, modern ClinVar assertions, or functional strength confidently. Consequently, Val60Leu should remain the reference, best-validated DFNA41 allele, and other alleles should be evaluated individually rather than assumed equivalent. (mittal2016molecularstructureand pages 10-11, wei2025singledosegenomeediting pages 18-18)

Risk factors

  • Genetic: A heterozygous pathogenic P2RX2 allele; an affected parent or other vertical family history.
  • Age: Thresholds worsen with age, particularly from adolescence through early/middle adulthood.
  • Noise: Occupational/recreational acoustic exposure is the best-supported modifiable factor. In the original family, noise-exposed carriers (n=12) had poorer 2–8-kHz thresholds than unexposed carriers (n=9; P=0.001). Exposures in construction trades during ages 12–25 were specifically reported. (yan2013mutationofthe pages 3-4, yan2013mutationofthe pages 2-3)
  • Sex: No sex-specific difference has been established.
  • Tobacco, alcohol, diet, exercise, pollution, infection, or ototoxic drugs: No DFNA41-specific risk estimates are available. General cochlear-risk counseling remains reasonable but must not be represented as disease-specific evidence.

Protective factors

No protective P2RX2 alleles, validated modifier genes, diets, drugs, or prophylactic agents have been demonstrated. Practical acoustic protection—avoiding hazardous exposure, reducing duration/intensity, and correctly using hearing protection—is biologically compelling because noise is a demonstrated phenotype modifier, although no prospective prevention trial has quantified benefit in DFNA41.

Causal gene–environment chain

P2RX2 Val60Leu → impaired ATP-gated cochlear channel activity → reduced purinergic adaptation during elevated sound → excessive acoustic stress and impaired ionic/homeostatic response → accelerated high-frequency threshold elevation and cochlear cellular injury. The human exposure association and mouse noise challenge jointly support this chain. (yan2013mutationofthe pages 1-2, yan2013mutationofthe pages 4-5, yan2013mutationofthe pages 5-6)

3. Phenotypes

Core human phenotype

Phenotype Characteristics Suggested HPO annotation
Sensorineural hearing impairment Defining manifestation; moderate-to-severe or severe with progression HP:0000407 Sensorineural hearing impairment
Bilateral/symmetric hearing impairment Bilateral and symmetrical in reported families HP:0011453 Bilateral hearing impairment; symmetry may require a qualifier
Progressive hearing impairment Chronic progression from adolescence, often stabilizing by the fourth decade HP:0008619 Progressive hearing impairment
Postlingual onset Usually 12–20 years in the defining families HP:0008504 Late-onset sensorineural hearing impairment or appropriate onset modifier
High-frequency hearing impairment Early sloping/high-frequency predominance, eventually all frequencies HP:0005101 High-frequency hearing impairment
Tinnitus Generally high-frequency tinnitus in affected members HP:0000360 Tinnitus
Increased noise susceptibility Acoustic exposure significantly worsens high-frequency thresholds Use exposure annotation plus noise-induced hearing-loss susceptibility; no exact HPO term was verified

The original report stated: “Audiologic evaluation of family members revealed bilateral and symmetrical sensorineural hearing loss, with age at onset ranging from 12 y to 20 y, generally accompanied by high-frequency tinnitus.” Hearing loss ultimately involved all frequencies. In the index family, it was severe—approximately 60–70 dB—by age 20, with relatively little subsequent progression; pooled thresholds declined until the fourth decade and then remained approximately stable. (yan2013mutationofthe pages 1-2, yan2013mutationofthe pages 2-3)

Vestibular phenotype

Vestibular dysfunction is prominent in the Val61Leu knock-in mouse, but a consistent vestibular disorder has not been established in the defining human families. It should therefore be recorded as a model phenotype, not a core human DFNA41 feature. (chen2021generationandcharacterization pages 1-2, chen2021generationandcharacterization pages 1-1)

Frequency and quality of life

Penetrance was 100% in the reported index pedigree, but exact frequencies of tinnitus, individual audiometric configurations, and vestibular symptoms are not robustly estimable from the few published families. No DFNA41-specific EQ-5D, SF-36, PROMIS, speech-recognition, education, employment, or caregiver-burden study was identified. Likely effects include impaired communication, speech understanding in noise, school/work participation, tinnitus burden, and eventual hearing-device dependence; these are clinically reasonable consequences of progressive sensorineural loss, not measured DFNA41-specific outcomes.

4. Genetic and molecular information

Gene and protein

  • Gene: P2RX2
  • Protein: P2X purinoceptor 2/P2X2 receptor
  • Reference transcript used in the foundational report: NM_174873
  • Reference protein cited in the mouse study: NP_733782
  • Variant: c.178G>T, p.(Val60Leu)
  • Genomic coordinate in the original report: hg19 chr12:133,196,029G>T
  • Variant class: missense SNV
  • Origin: constitutional/germline
  • Inheritance: autosomal dominant
  • Population frequency: absent from the historical 7,000-control dataset; contemporary gnomAD frequency was not independently verified here. (yan2013mutationofthe pages 1-2, yan2013mutationofthe pages 2-3, chen2021generationandcharacterization pages 2-3)

The Val60 residue is highly conserved across vertebrates. The variant has strong pathogenic evidence: cosegregation, two unrelated families with concordant phenotype, extreme rarity, functional loss, and matching animal phenotypes. A clinical laboratory should nevertheless apply current ACMG/AMP hearing-loss specifications and report its current ClinVar classification/accession rather than copy a historical label uncritically.

Functional consequence

Wild-type P2X2 channels responded to ATP with inward current; 1 mM ATP produced a mean current of 2.17 ± 0.46 nA in wild-type-transfected HEK293 cells (n=16), whereas Val60Leu-transfected cells showed no response (n=15). Mutant channels also lacked ATP-stimulated FM1-43 permeability. Coexpression of wild-type and mutant subunits—modeling heterozygosity—reduced ATP-activated permeability by approximately 60%. Both proteins targeted the plasma membrane, arguing for defective gating/channel function rather than simple trafficking failure. (yan2013mutationofthe pages 3-4, yan2013mutationofthe pages 2-3)

The literature uses both “loss of function” and, in a later editing paper, “gain-of-function mutation.” The direct electrophysiology supports loss of ATP-activated channel function with a dominant interfering effect in heteromeric trimers. “Dominant-negative” is mechanistically plausible but should be used cautiously unless a variant-specific clinical laboratory or functional study explicitly adopts that classification. (yan2013mutationofthe pages 4-5, wei2025singledosegenomeediting pages 1-2)

Other genomic and regulatory information

No recurrent CNV, translocation, inversion, aneuploidy, repeat expansion, mitochondrial lesion, somatic mosaicism, or epigenetic signature is established as the cause of DFNA41. No validated modifier gene, methylation biomarker, chromatin abnormality, or disease-specific transcriptomic, proteomic, metabolomic, or lipidomic signature was identified.

5. Environmental information

Noise is the only non-genetic exposure with direct DFNA41-specific human evidence. Affected carriers may be harmed by exposure levels tolerated by noncarriers, and the original authors discussed susceptibility even around occupational levels conventionally regarded as acceptable. (yan2013mutationofthe pages 5-6)

There is no evidence that infection causes or triggers DFNA41. Smoking, alcohol, diet, physical activity, radiation, air pollution, and occupational chemicals have not been studied specifically. Ototoxic medications may independently injure hearing, but a P2RX2-specific pharmacogenetic interaction has not been demonstrated.

6. Mechanism and pathophysiology

Upstream molecular defect

P2X2 is a trimeric, extracellular ATP-gated nonselective cation channel. In the inner ear it is implicated in sound-transduction regulation, auditory neurotransmission, outer-hair-cell electromotility, gap-junction-associated homeostasis, and potassium recycling. Extracellular ATP released during acoustic stress activates P2 receptors in sensory, supporting, and neural tissues, reducing cochlear sensitivity and contributing to adaptation. (yan2013mutationofthe pages 1-2, mittal2016molecularstructureand pages 10-11)

Causal chain

  1. Germline P2RX2 Val60Leu alters a conserved extracellular/transmembrane-coupled gating region.
  2. Mutant subunits reach the membrane but fail to generate normal ATP-evoked current; mixed wild-type/mutant trimers have reduced permeability.
  3. Cochlear sensory and supporting cells cannot mount normal ATP-dependent adaptation and ionic shunting during sustained sound.
  4. Repeated physiological, age-related, and acoustic stress leads to impaired hair-cell/synaptic function.
  5. Model pathology includes abnormal inner-hair-cell morphology, disrupted ribbon-synapse distribution, hair/supporting-cell loss, and spiral-ganglion-neuron loss.
  6. Clinically this produces progressive, initially high-frequency sensorineural hearing loss, accelerated by noise. (yan2013mutationofthe pages 4-5, chen2021generationandcharacterization pages 2-3)

Suggested ontology terms

  • GO molecular function: extracellular ATP-gated cation channel activity; ligand-gated ion-channel activity; purinergic nucleotide receptor activity.
  • GO biological process: ion transmembrane transport; cellular response to ATP; potassium-ion homeostasis; sensory perception of sound; auditory receptor-cell development; chemical synaptic transmission; response to acoustic stimulus.
  • GO cellular component: plasma membrane; stereocilium membrane where supported; Golgi apparatus; mitochondrion; presynaptic ribbon/synaptic region.
  • Cell Ontology: inner hair cell; outer hair cell; cochlear supporting cell; spiral ganglion neuron; vestibular hair cell.

The organelle localization reported in mouse fibroblasts—plasma membrane, Golgi, and mitochondria—does not by itself establish mitochondrial dysfunction as a human disease mechanism. Likewise, inflammation, apoptosis, oxidative stress, and immune activation are plausible downstream pathways in acoustic injury but have not been specifically demonstrated as primary DFNA41 mechanisms.

Molecular profiling and advanced technologies

No DFNA41 single-cell atlas, spatial-transcriptomic dataset, unbiased proteome/metabolome, or multi-omics patient cohort was found. Available advanced platforms are targeted: electrophysiology, immunolocalization, patient-derived hiPSCs, CRISPR-engineered isogenic lines, targeted sequencing, and in-vivo allele editing. Patient-derived nonintegrating hiPSCs were generated from urine samples of three family members, and CRISPR plus single-stranded donor oligonucleotides generated homozygous isogenic mutant cells. These are mechanistic models, not diagnostic assays or therapies. (dong2019efficientintroductionof pages 1-3)

7. Anatomical structures affected

The primary organ is the inner ear, specifically the cochlea. Relevant structures include the organ of Corti, inner and outer hair cells, supporting epithelium, spiral ganglion and auditory nerve pathway, lateral-wall homeostatic system, and ribbon synapses. P2X2 expression in the knock-in study was strong in the organ of Corti, spiral ganglion, and crista ampullaris; within the cochlea it was present in inner/outer hair cells, supporting cells, and spiral ganglion neurons. (chen2021generationandcharacterization pages 2-3)

Suggested anatomy annotations include UBERON: cochlea, organ of Corti, inner ear, spiral ganglion, auditory hair cell, and crista ampullaris. The human hearing loss is bilateral and symmetric. Temporal-bone CT in one affected person was normal, consistent with a molecular/cellular rather than gross malformation disorder. No secondary systemic-organ involvement has been established. (yan2013mutationofthe pages 1-2, yan2013mutationofthe pages 2-3)

8. Temporal development

  • Onset: Insidious, postlingual, usually 12–20 years in the original families.
  • Early stage: High-frequency threshold elevation and tinnitus; speech understanding in noise may deteriorate before broad-frequency disability.
  • Intermediate stage: Progressive involvement of additional frequencies; approximately 60–70-dB severity by age 20 in the index pedigree.
  • Later stage: Mean thresholds declined until approximately the fourth decade and then were comparatively stable, although individual trajectories and noise exposure varied.
  • Course: Chronic/lifelong; neither episodic nor relapsing-remitting.
  • Remission: No spontaneous or treatment-induced biological remission documented.
  • Critical period: Early identification, before extensive cochlear degeneration or hazardous noise exposure, is the rational intervention window. Mouse editing produced broader frequency rescue when delivered earlier, but the human window is unknown. (yan2013mutationofthe pages 2-3, wei2025singledosegenomeediting pages 1-2)

9. Inheritance and population

DFNA41 is autosomal dominant: each child of a heterozygous affected individual has a theoretical 50% probability of inheriting the familial variant. Reported penetrance for Val60Leu was 100% in the index family, but this estimate may not generalize to every P2RX2 allele or age. Expressivity varies with age and noise exposure. No anticipation, repeat expansion, parent-of-origin effect, or established germline mosaicism has been reported. (yan2013mutationofthe pages 2-3)

Prevalence and incidence per 100,000 are unknown. The small number of reported families and absence from 7,000 historical controls indicate an ultrarare disorder. The reference Val60Leu allele was initially found in two Chinese families; this does not prove a founder effect because shared ancestry/haplotype evidence was not established. Other population reports suggest allelic and geographic expansion, but robust ancestry-specific frequencies are unavailable. No sex bias is expected for an autosomal disorder and none has been demonstrated. Consanguinity is not etiologically relevant to the dominant inheritance pattern, although it may coexist incidentally.

10. Diagnostics

Clinical evaluation

Diagnosis requires:

  1. Personal and three-generation family history, including age at onset, tinnitus, vestibular symptoms, occupational/recreational noise, and ototoxic exposure.
  2. Otoscopy and middle-ear assessment to exclude conductive disease.
  3. Bilateral pure-tone audiometry, bone conduction, speech reception/recognition, and serial testing to document progression.
  4. Tympanometry; otoacoustic emissions and auditory brainstem responses when age, reliability, or auditory-neuropathy differential warrants them.
  5. Vestibular examination/testing only if symptoms are present or for detailed phenotyping.
  6. Imaging when cochlear implantation, asymmetry, neurologic signs, or another structural disorder is suspected—not as a molecular confirmation test. One affected carrier had normal temporal bones on CT. (yan2013mutationofthe pages 2-3)

No blood chemistry, urine assay, enzyme assay, biopsy, histopathology, circulating protein, metabolite, or imaging biomarker is diagnostic.

Genetic testing

A comprehensive hearing-loss NGS panel containing P2RX2 is generally the most efficient first molecular test. Sequence analysis must detect SNVs and small indels; exon-level CNV analysis is useful for the broader differential, although no recurrent P2RX2 CNV is established. Familial Val60Leu can be confirmed by targeted Sanger sequencing. WES or WGS is appropriate when a panel is negative, phenotype is atypical, structural/noncoding variation is suspected, or reanalysis is anticipated. WGS offers more uniform coverage and noncoding/structural-variant detection but has no proven DFNA41-specific yield advantage.

CMA, karyotyping, FISH, mitochondrial sequencing, and repeat-expansion testing are not routine tests for classic DFNA41; deploy them only when the phenotype or family history suggests another diagnosis. RNA sequencing is research-level because no validated P2RX2 splicing biomarker exists.

Pathogenic/likely pathogenic results should be confirmed and segregated in relatives. A VUS must not establish diagnosis or direct predictive testing without additional evidence.

Differential diagnosis

The principal differential includes other autosomal dominant progressive nonsyndromic hearing losses—particularly KCNQ4/DFNA2, WFS1/DFNA6/14/38, TECTA/DFNA8/12, ACTG1/DFNA20/26, POU4F3/DFNA15, MYO6/DFNA22, EYA4/DFNA10—and acquired noise-induced, ototoxic, infectious, autoimmune, structural, and age-related hearing loss. The combination of adolescent onset, bilateral symmetric progression, vertical inheritance, and disproportionate noise susceptibility suggests but does not uniquely identify DFNA41. A 2023 review emphasized that dominant nonsyndromic loss is usually bilateral, postlingual, high-frequency, and progressive, underscoring the need for molecular rather than phenotype-only diagnosis. (alde2023autosomaldominantnonsyndromic pages 16-17)

Screening

Universal newborn physiologic hearing screening may be normal because DFNA41 is commonly postlingual. The key strategy is cascade genetic testing after identifying a familial pathogenic variant, followed by baseline and serial audiometry in carriers. Predictive testing of minors can be clinically useful because noise avoidance and auditory surveillance are actionable during childhood/adolescence.

11. Outcome and prognosis

DFNA41 is not known to reduce survival or life expectancy, and disease-specific mortality is not reported. Morbidity is auditory: progressive communication disability, tinnitus, reduced speech understanding—especially in noise—and possible eventual dependence on amplification or implantation. Human vestibular disability is insufficiently characterized.

Untreated sensorineural loss does not biologically recover. Hearing aids and cochlear implants can improve function but do not correct the underlying channel defect. Prognosis depends on baseline thresholds, age, rate of progression, speech recognition, acoustic exposure, and timely rehabilitation. The familial P2RX2 genotype predicts susceptibility but is not a validated quantitative prognostic biomarker.

12. Treatment

Current standard management

There is no approved DFNA41-specific pharmacotherapy and no established P2RX2-directed pharmacogenomic algorithm. Management is individualized:

  • Regular audiology, with shorter intervals during childhood, after threshold change, or after major noise exposure.
  • Hearing aids when thresholds or communication needs warrant them.
  • Remote microphones, classroom/workplace accommodations, captioning, and auditory/speech-language rehabilitation.
  • Tinnitus counseling and evidence-based tinnitus management.
  • Cochlear-implant assessment for severe-to-profound loss with inadequate aided speech understanding.
  • Genetic counseling and cascade testing.
  • Strict acoustic-risk reduction.

Suggested NCIT concepts include Hearing Aid Device, Cochlear Implantation, Auditory Rehabilitation, Speech Therapy, Genetic Counseling, and Genetic Testing. No DFNA41-specific response rate or adverse-event dataset exists; outcomes should be drawn from the applicable device and rehabilitation population rather than attributed to this genotype.

Experimental genome editing

A 2025 JCI study used local round-window-membrane injection plus canal fenestration to deliver AAV2–Staphylococcus aureus Cas9–sgRNA into adult P2rx2Val61Leu/+ mice. The strategy disrupted the mutant allele while preserving wild type. In primary cells, SaCas9–sgRNA-1 produced 75.01% ± 4.55% mutant-allele indels versus 0.45% ± 0.39% on the wild-type allele; 85.1% of indels were frameshifting. In vivo whole-cochlea indels were 2.62% ± 0.64%, while mutant-transcript and isolated-hair-cell analyses indicated approximately 28% editing of P2rx2-expressing cells and 26.96% ± 4.2% mutant-allele editing in isolated hair cells. No CIRCLE-seq off-target site beyond the target was found in the reported cell assay, and no notable AAV integration was detected at the cochlear target under the therapeutic conditions. (wei2025singledosegenomeediting pages 5-7, wei2025singledosegenomeediting pages 2-5)

The abstract states that editing “effectively restores long-term auditory and vestibular function” and protects mice from the heightened noise-induced phenotype. Juvenile intervention rescued a broader frequency range, and a human-Val60Leu-specific guide was identified. Nevertheless, this is mouse evidence: inner-ear surgical delivery, durability, immune response, off-target detection sensitivity, large rearrangements, human cochlear coverage, and allele specificity require further validation. No DFNA41 human interventional trial or NCT identifier was found in the ClinicalTrials.gov search. (wei2025singledosegenomeediting pages 1-2)

13. Prevention

Primary prevention

The inherited variant cannot presently be prevented in an individual after conception. For carriers, the most important modifiable action is prevention of avoidable acoustic injury: engineering controls, lower volume, shorter exposure, distance from sound sources, correctly fitted hearing protection, and occupational-health review. Avoid unnecessary ototoxic exposure and monitor hearing when an ototoxic drug is medically essential, although no P2RX2-specific drug interaction has been shown.

Secondary prevention

  • Cascade testing of at-risk relatives.
  • Baseline audiometry before expected onset.
  • Periodic surveillance to detect subtle high-frequency loss.
  • Early amplification and educational/work accommodations.
  • Prompt reassessment after tinnitus, perceived decline, or significant noise exposure.

Tertiary prevention

Appropriate hearing technology, communication rehabilitation, tinnitus care, fall/vestibular assessment when symptomatic, and psychosocial/occupational accommodations reduce disability.

Reproductive counseling

Counsel regarding the 50% transmission probability, variable severity and noise-modified expressivity, natural conception with prenatal diagnosis, and IVF with PGT-M where legally and ethically available. Carrier screening is not the appropriate concept for an autosomal dominant disorder; targeted predictive testing of relatives is more relevant. There is no applicable vaccine, anti-infective prophylaxis, or population-wide DFNA41 screening program.

14. Other species and natural disease

P2rx2 is evolutionarily conserved in vertebrates, and Val60/61 lies in a highly conserved region. Relevant taxa include Homo sapiens (NCBI Taxon 9606), Mus musculus (10090), Rattus norvegicus (10116), and Danio rerio (7955). A naturally occurring companion-animal, livestock, or wildlife disorder confidently homologous to human DFNA41 was not identified. There is no zoonotic or cross-species transmission because this is an inherited channelopathy, not an infection.

Comparative work demonstrates conservation of cochlear P2X2-mediated acoustic adaptation, but species differ in cochlear maturation and disease timing. Veterinary breed/VBO annotations are therefore unavailable.

15. Model organisms and experimental systems

P2rx2-null mouse

P2rx2-knockout mice develop progressive hearing loss, particularly in the high-frequency basal cochlea, and exaggerated noise-induced threshold shifts. At advanced age they show degeneration involving hair cells, supporting cells, and spiral ganglion neurons. After early moderate noise exposure, knockout mice had approximately 13-dB greater thresholds at 20–36 kHz than controls. This model establishes the protective function of P2X2 but models complete loss, not the exact heterozygous human allele. (yan2013mutationofthe pages 1-2, yan2013mutationofthe pages 4-5)

P2rx2Val61Leu knock-in mouse

The mouse homolog of human Val60 is Val61. Heterozygous knock-in mice developed hearing loss by postnatal day 21 and deafness by approximately six months, accompanied by vestibular dysfunction and progressive inner-hair-cell and ribbon-synapse abnormalities. Expression was seen in inner/outer hair cells, supporting cells, spiral ganglion neurons, and crista ampullaris. This is the principal allele-specific model and the platform used for genome editing. Its limitation is substantially earlier and faster progression than the usual human 12–20-year onset. (chen2021generationandcharacterization pages 1-2, chen2021generationandcharacterization pages 1-1, chen2021generationandcharacterization pages 2-3)

Cellular models

  • HEK293 cells: ATP-current electrophysiology.
  • MDCK-II cells: ATP-dependent FM1-43 permeability.
  • Rat organ-of-Corti cultures: receptor targeting/localization.
  • Patient-derived hiPSCs and CRISPR-generated isogenic mutant hiPSCs: human genetic background and differentiation platform.
  • HEI-OC1 cochlear cells and mouse fibroblasts: allele-specific editor screening and off-target assessment. (yan2013mutationofthe pages 2-3, dong2019efficientintroductionof pages 1-3, wei2025singledosegenomeediting pages 2-5)

The hiPSCs were described as “good models to investigate the pathological mechanisms,” but they do not reproduce the mature cochlear architecture, tonotopy, acoustic mechanics, or lifelong exposure history. Organoids, single-cell profiling, and spatial assays could help bridge that gap.

Evidence hierarchy, recent developments, and gaps

The decisive human evidence remains the 2013 genetic-functional study; no 2023–2024 primary study materially redefined the DFNA41 phenotype or causal allele in the retrieved corpus. The most relevant recent review context is the 2023 synthesis of autosomal dominant nonsyndromic hearing loss, while the major disease-specific translational advance was published in 2025, after submission in October 2024. (alde2023autosomaldominantnonsyndromic pages 16-17, wei2025singledosegenomeediting pages 1-2)

Key unresolved areas are disease prevalence, complete allelic spectrum, contemporary ClinVar/gnomAD curation for each allele, prospective natural history, speech-recognition and quality-of-life outcomes, human vestibular involvement, modifiers other than noise, biomarkers, optimal surveillance intervals, genotype-specific implant outcomes, and human safety/efficacy of allele editing.

Principal references

  1. Yan D, et al. Mutation of the ATP-gated P2X2 receptor leads to progressive hearing loss and increased susceptibility to noise. PNAS. Published February 5, 2013;110:2228–2233. DOI/URL: https://doi.org/10.1073/pnas.1222285110. The abstract directly states that Val60Leu “abolishes two hallmark features” of P2X2 receptors and that noise worsened hearing in heterozygous relatives. (yan2013mutationofthe pages 1-2, yan2013mutationofthe pages 2-3)
  2. Housley GD, et al. ATP-gated ion channels mediate adaptation to elevated sound levels. PNAS. Published 2013;110:7494–7499. DOI/URL: https://doi.org/10.1073/pnas.1222295110. This supplies complementary model evidence for P2X2-mediated acoustic adaptation. (yan2013mutationofthe pages 1-2)
  3. Dong Y, et al. Efficient introduction of an isogenic homozygous mutation to induced pluripotent stem cells from a hereditary hearing loss family using CRISPR/Cas9 and single-stranded donor oligonucleotides. J Int Med Res. Published 2019;47:1717–1730. DOI/URL: https://doi.org/10.1177/0300060519829990. (dong2019efficientintroductionof pages 1-3)
  4. Chen X, et al. Generation and characterization of a P2rx2 V60L mouse model for DFNA41. Human Molecular Genetics. Published March 2021;30:985–995. DOI/URL: https://doi.org/10.1093/hmg/ddab077. The abstract reports hearing loss at day 21, deafness by six months, vestibular dysfunction, and ribbon-synapse abnormalities. (chen2021generationandcharacterization pages 1-2, chen2021generationandcharacterization pages 2-3)
  5. Vlajkovic SM, Thorne PR. Purinergic Signalling in the Cochlea. International Journal of Molecular Sciences. Published November 2022;23:14874. DOI/URL: https://doi.org/10.3390/ijms232314874. Review evidence for cochlear ATP signaling and acoustic adaptation.
  6. Aldè M, et al. Autosomal Dominant Non-Syndromic Hearing Loss (DFNA): A Comprehensive Narrative Review. Biomedicines. Published June 2023;11:1616. DOI/URL: https://doi.org/10.3390/biomedicines11061616. (alde2023autosomaldominantnonsyndromic pages 16-17)
  7. Wei W, et al. Single-dose genome editing therapy rescues auditory and vestibular functions in adult mice with DFNA41 deafness. Journal of Clinical Investigation. Published August 14, 2025;135:e187872. DOI/URL: https://doi.org/10.1172/JCI187872. Model-only therapeutic evidence; no human efficacy is established. (wei2025singledosegenomeediting pages 5-7, wei2025singledosegenomeediting pages 2-5, wei2025singledosegenomeediting pages 1-2)

References

  1. (yan2013mutationofthe pages 1-2): Denise Yan, Yan Zhu, Tom Walsh, Dinghua Xie, Huijun Yuan, Asli Sirmaci, Taro Fujikawa, Ann Chi Yan Wong, Tze L. Loh, Lilin Du, M’hamed Grati, Srdjan M. Vlajkovic, Susan Blanton, Allen F. Ryan, Zheng-Yi Chen, Peter R. Thorne, Bechara Kachar, Mustafa Tekin, Hong-Bo Zhao, Gary D. Housley, Mary-Claire King, and Xue Z. Liu. Mutation of the atp-gated p2x2 receptor leads to progressive hearing loss and increased susceptibility to noise. Proceedings of the National Academy of Sciences, 110:2228-2233, Jan 2013. URL: https://doi.org/10.1073/pnas.1222285110, doi:10.1073/pnas.1222285110. This article has 196 citations and is from a highest quality peer-reviewed journal.

  2. (yan2013mutationofthe pages 2-3): Denise Yan, Yan Zhu, Tom Walsh, Dinghua Xie, Huijun Yuan, Asli Sirmaci, Taro Fujikawa, Ann Chi Yan Wong, Tze L. Loh, Lilin Du, M’hamed Grati, Srdjan M. Vlajkovic, Susan Blanton, Allen F. Ryan, Zheng-Yi Chen, Peter R. Thorne, Bechara Kachar, Mustafa Tekin, Hong-Bo Zhao, Gary D. Housley, Mary-Claire King, and Xue Z. Liu. Mutation of the atp-gated p2x2 receptor leads to progressive hearing loss and increased susceptibility to noise. Proceedings of the National Academy of Sciences, 110:2228-2233, Jan 2013. URL: https://doi.org/10.1073/pnas.1222285110, doi:10.1073/pnas.1222285110. This article has 196 citations and is from a highest quality peer-reviewed journal.

  3. (yan2013mutationofthe pages 4-5): Denise Yan, Yan Zhu, Tom Walsh, Dinghua Xie, Huijun Yuan, Asli Sirmaci, Taro Fujikawa, Ann Chi Yan Wong, Tze L. Loh, Lilin Du, M’hamed Grati, Srdjan M. Vlajkovic, Susan Blanton, Allen F. Ryan, Zheng-Yi Chen, Peter R. Thorne, Bechara Kachar, Mustafa Tekin, Hong-Bo Zhao, Gary D. Housley, Mary-Claire King, and Xue Z. Liu. Mutation of the atp-gated p2x2 receptor leads to progressive hearing loss and increased susceptibility to noise. Proceedings of the National Academy of Sciences, 110:2228-2233, Jan 2013. URL: https://doi.org/10.1073/pnas.1222285110, doi:10.1073/pnas.1222285110. This article has 196 citations and is from a highest quality peer-reviewed journal.

  4. (chen2021generationandcharacterization pages 2-3): Xiaoya Chen, Clemer Abad, Zheng-yi Chen, Juan I Young, Channabasavaiah B Gurumurthy, Katherina Walz, and Xue Zhong Liu. Generation and characterization of a p2rx2 v60l mouse model for dfna41. Human molecular genetics, 30:985-995, Mar 2021. URL: https://doi.org/10.1093/hmg/ddab077, doi:10.1093/hmg/ddab077. This article has 10 citations and is from a domain leading peer-reviewed journal.

  5. (wei2025singledosegenomeediting pages 2-5): Wei Wei, Wenliang Zhu, Stewart Silver, Ariel M. Armstrong, Fletcher S. Robbins, Arun Prabhu Rameshbabu, Katherina Walz, Yizhou Quan, Wan Du, Yehree Kim, Artur A. Indzhykulian, Yilai Shu, Xue-Zhong Liu, and Zheng-Yi Chen. Single-dose genome editing therapy rescues auditory and vestibular functions in adult mice with dfna41 deafness. Journal of Clinical Investigation, Aug 2025. URL: https://doi.org/10.1172/jci187872, doi:10.1172/jci187872. This article has 5 citations and is from a highest quality peer-reviewed journal.

  6. (wei2025singledosegenomeediting pages 1-2): Wei Wei, Wenliang Zhu, Stewart Silver, Ariel M. Armstrong, Fletcher S. Robbins, Arun Prabhu Rameshbabu, Katherina Walz, Yizhou Quan, Wan Du, Yehree Kim, Artur A. Indzhykulian, Yilai Shu, Xue-Zhong Liu, and Zheng-Yi Chen. Single-dose genome editing therapy rescues auditory and vestibular functions in adult mice with dfna41 deafness. Journal of Clinical Investigation, Aug 2025. URL: https://doi.org/10.1172/jci187872, doi:10.1172/jci187872. This article has 5 citations and is from a highest quality peer-reviewed journal.

  7. (yan2013mutationofthe pages 5-6): Denise Yan, Yan Zhu, Tom Walsh, Dinghua Xie, Huijun Yuan, Asli Sirmaci, Taro Fujikawa, Ann Chi Yan Wong, Tze L. Loh, Lilin Du, M’hamed Grati, Srdjan M. Vlajkovic, Susan Blanton, Allen F. Ryan, Zheng-Yi Chen, Peter R. Thorne, Bechara Kachar, Mustafa Tekin, Hong-Bo Zhao, Gary D. Housley, Mary-Claire King, and Xue Z. Liu. Mutation of the atp-gated p2x2 receptor leads to progressive hearing loss and increased susceptibility to noise. Proceedings of the National Academy of Sciences, 110:2228-2233, Jan 2013. URL: https://doi.org/10.1073/pnas.1222285110, doi:10.1073/pnas.1222285110. This article has 196 citations and is from a highest quality peer-reviewed journal.

  8. (mittal2016molecularstructureand pages 10-11): Rahul Mittal, Brandon Chan, M'hamed Grati, Jeenu Mittal, Kunal Patel, Luca H. Debs, Amit P. Patel, Denise Yan, Prem Chapagain, and Xue Zhong Liu. Molecular structure and regulation of p2x receptors with a special emphasis on the role of p2x2 in the auditory system. Journal of Cellular Physiology, 231:1656-1670, Aug 2016. URL: https://doi.org/10.1002/jcp.25274, doi:10.1002/jcp.25274. This article has 26 citations and is from a peer-reviewed journal.

  9. (alde2023autosomaldominantnonsyndromic pages 16-17): Mirko Aldè, Giovanna Cantarella, Diego Zanetti, Lorenzo Pignataro, Ignazio La Mantia, Luigi Maiolino, Salvatore Ferlito, Paola Di Mauro, Salvatore Cocuzza, Jérôme René Lechien, Giannicola Iannella, Francois Simon, and Antonino Maniaci. Autosomal dominant non-syndromic hearing loss (dfna): a comprehensive narrative review. Biomedicines, 11:1616, Jun 2023. URL: https://doi.org/10.3390/biomedicines11061616, doi:10.3390/biomedicines11061616. This article has 65 citations.

  10. (chen2021generationandcharacterization pages 1-2): Xiaoya Chen, Clemer Abad, Zheng-yi Chen, Juan I Young, Channabasavaiah B Gurumurthy, Katherina Walz, and Xue Zhong Liu. Generation and characterization of a p2rx2 v60l mouse model for dfna41. Human molecular genetics, 30:985-995, Mar 2021. URL: https://doi.org/10.1093/hmg/ddab077, doi:10.1093/hmg/ddab077. This article has 10 citations and is from a domain leading peer-reviewed journal.

  11. (chen2021generationandcharacterization pages 1-1): Xiaoya Chen, Clemer Abad, Zheng-yi Chen, Juan I Young, Channabasavaiah B Gurumurthy, Katherina Walz, and Xue Zhong Liu. Generation and characterization of a p2rx2 v60l mouse model for dfna41. Human molecular genetics, 30:985-995, Mar 2021. URL: https://doi.org/10.1093/hmg/ddab077, doi:10.1093/hmg/ddab077. This article has 10 citations and is from a domain leading peer-reviewed journal.

  12. (dong2019efficientintroductionof pages 1-3): Yunpeng Dong, Tao Peng, Weijing Wu, Donghui Tan, Xuezhong Liu, and Dinghua Xie. Efficient introduction of an isogenic homozygous mutation to induced pluripotent stem cells from a hereditary hearing loss family using crispr/cas9 and single-stranded donor oligonucleotides. The Journal of International Medical Research, 47:1717-1730, Feb 2019. URL: https://doi.org/10.1177/0300060519829990, doi:10.1177/0300060519829990. This article has 12 citations.

  13. (wei2025singledosegenomeediting pages 5-7): Wei Wei, Wenliang Zhu, Stewart Silver, Ariel M. Armstrong, Fletcher S. Robbins, Arun Prabhu Rameshbabu, Katherina Walz, Yizhou Quan, Wan Du, Yehree Kim, Artur A. Indzhykulian, Yilai Shu, Xue-Zhong Liu, and Zheng-Yi Chen. Single-dose genome editing therapy rescues auditory and vestibular functions in adult mice with dfna41 deafness. Journal of Clinical Investigation, Aug 2025. URL: https://doi.org/10.1172/jci187872, doi:10.1172/jci187872. This article has 5 citations and is from a highest quality peer-reviewed journal.

  14. (wei2025singledosegenomeediting pages 18-18): Wei Wei, Wenliang Zhu, Stewart Silver, Ariel M. Armstrong, Fletcher S. Robbins, Arun Prabhu Rameshbabu, Katherina Walz, Yizhou Quan, Wan Du, Yehree Kim, Artur A. Indzhykulian, Yilai Shu, Xue-Zhong Liu, and Zheng-Yi Chen. Single-dose genome editing therapy rescues auditory and vestibular functions in adult mice with dfna41 deafness. Journal of Clinical Investigation, Aug 2025. URL: https://doi.org/10.1172/jci187872, doi:10.1172/jci187872. This article has 5 citations and is from a highest quality peer-reviewed journal.

  15. (yan2013mutationofthe pages 3-4): Denise Yan, Yan Zhu, Tom Walsh, Dinghua Xie, Huijun Yuan, Asli Sirmaci, Taro Fujikawa, Ann Chi Yan Wong, Tze L. Loh, Lilin Du, M’hamed Grati, Srdjan M. Vlajkovic, Susan Blanton, Allen F. Ryan, Zheng-Yi Chen, Peter R. Thorne, Bechara Kachar, Mustafa Tekin, Hong-Bo Zhao, Gary D. Housley, Mary-Claire King, and Xue Z. Liu. Mutation of the atp-gated p2x2 receptor leads to progressive hearing loss and increased susceptibility to noise. Proceedings of the National Academy of Sciences, 110:2228-2233, Jan 2013. URL: https://doi.org/10.1073/pnas.1222285110, doi:10.1073/pnas.1222285110. This article has 196 citations and is from a highest quality peer-reviewed journal.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 9
Resolved 9
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 9
On topic 7
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 14
Resolved 14
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0

Every term resolved, and every label the report gave matched.